Sign up to receive free email alerts when patent applications with chosen keywords are publishedSIGN UP

Abstract:

The present invention relates to compounds of formula (I): Wherein
A1, A2, A3, A4, G1, L, Y1, Y2,
Y3, Y4, R1, R2, R3 and R4 are as defined in
claim 1; or a salt or N-oxide thereof. Furthermore, the present invention
relates to intermediates for preparing compounds of formula (I), to
compositions comprising them and to methods of using them to combat and
control insect, acarine, nematode and mollusc pests.
##STR00001##

Claims:

1. A compound of formula (I): ##STR00235## wherein A1, A2,
A3 and A4 are independently of one another C--H, C--R5, or
nitrogen; G1 is oxygen or sulfur; L is a single bond or
C1-C8alkylene; R1 is hydrogen, C1-C8alkyl,
C1-C8alkylcarbonyl-, C1-C8alkoxy,
C1-C8alkoxy-C1-C8alkyl or
C1-C8alkoxycarbonyl-; R2 is hydrogen,
C1-C8haloalkyl or C1-C8alkyl; R3 is
C1-C8haloalkyl; R4 is aryl or aryl substituted by one to
three R6, or R4 is heterocyclyl or heterocyclyl substituted by
one to three R6; each R5 is independently halogen, cyano,
nitro, C1-C8alkyl, C3-C8cycloalkyl,
C1-C8haloalkyl, C2-C8alkenyl,
C2-C8haloalkenyl, C2-C8alkynyl,
C2-C8haloalkynyl, C1-C8alkoxy,
C1-C8haloalkoxy, C1-C8alkoxycarbonyl-, or two R5
on adjacent carbon atoms together form a --CH═CH--CH═CH-- bridge
or a --N═CH--CH═CH-- bridge; each R6 is independently
halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl,
C1-C8alkoxy, or C1-C8haloalkoxy; Y1 is
CR7R8 or C═O; Y2, Y3 and Y4 are
independently CR7R8, C═O, N--R9, O, S, SO or SO2;
wherein at least two adjacent ring atoms in the ring formed by Y1,
Y2, Y3 and Y4 are heteroatoms; each R7 and R8 is
independently hydrogen, halogen, C1-C8alkyl, or
C1-C8haloalkyl; each R9 is independently hydrogen, cyano,
cyano-C1-C8alkyl, C1-C8alkyl,
C1-C8haloalkyl, C3-C8cycloalkyl,
C3-C8cycloalkyl where one carbon atom is replaced by O, S, S(O)
or SO2, or C3-C8cycloalkyl-C1-C8alkyl,
C3-C8cycloalkyl-C1-C8alkyl where one carbon atom in
the cycloalkyl group is replaced by O, S, S(O) or SO2, or
C3-C8cycloalkyl-C1-C8haloalkyl, Cr
C8hydroxyalkyl, C1-C8alkoxy-C1-C8alkyl,
C2-C8alkenyl, C2-C8haloalkenyl,
C2-C8alkynyl, C2-C8haloalkynyl, phenyl, phenyl
substituted by one to three R10, phenyl-C1-C4alkyl,
phenyl-C1-C4alkyl wherein the phenyl moiety is substituted by
one to three R10, 5-6 membered heteroaryl-C1-C4alkyl or
5-6 membered heteroaryl-C1-C4alkyl wherein the heteroaryl
moiety is substituted by one to three R10,
C1-C4alkyl-(C1-C4alkyl-O--N═)C--CH2--; each
R10 is independently halogen, cyano, nitro, C1-C8alkyl,
C1-C8haloalkyl, C1-C8alkoxy, or
C1-C8haloalkoxY; or a salt or N-oxide thereof.

2. A compound according to claim 1, wherein the compound is a compound of
formula (Ia.C): ##STR00236## wherein R2 is hydrogen or
C1-C4 alkyl; R3 is C1-C4 haloalkyl; R4 is
phenyl, or phenyl substituted by one to three R6; R5 is
halogen, nitro, C1-C4alkyl, C3-C4cycloalkyl,
C2-C4alkenyl or C1-C4haloalkyl; A3 and A4
are independently C--H or N; L is a bond or methylene.

3. A compound according to claim 1, wherein Y1 is CR7R.sup.8.

4. A compound according to claim 1, wherein two of Y2, Y3 and
Y4 in the grouping --Y2--Y3--Y4-- together are
--S--S--, --S--SO--, --SO--SO--, --SO--SO2--,
--SO2--SO2--, --O--N(--R9)--, --O--S--, --O--SO--,
--O--SO2--, --N(--R9)--N(--R9)--, --N(--R9)--S--,
--N(--R9)--S(O)-- or --N(--R9)--SO.sub.2--.

11. A compound according to claim 1, wherein the grouping
--Y2--Y3--Y4-- is selected from
--O--N(--R9)--C(═O)--, --S--S--C(R7)(R8)--,
--SO2--N(--R9)--C(R7)(R8)--,
--C(R7)(R8)--N(--R9)--O--, --C(═O)--N(--R9)--O--,
--SO--O--C(R7)(R8)-- and --C(═O)--N(--R9)--O--.

12. A compound according to claim 1, wherein the grouping
--Y2--Y3--Y4-- is --O--N(--R9)--C(═O)-- or
--SO--O--C(R7)(R8)--.

13. A compound according to claim 1, wherein R9 is hydrogen,
cyano-C1-C8alkyl, C1-C8alkyl,
C3-C8cycloalkyl, C3-C8cycloalkyl where one carbon
atom in the cycloalkyl group is replaced by O, S, S(O) or SO2, or
C1-C8haloalkyl, C1-C8hydroxyalkyl,
C2-C8alkenyl, C2-C8alkynyl,
phenyl-C1-C4alkyl or phenyl-Cr C4alkyl wherein the
phenyl moiety is substituted by one to three R10, 5-6 membered
heteroaryl-C1-C4alkyl or 5-6 membered
heteroaryl-C1-C4alkyl wherein the heteroaryl moiety is
substituted by one to three R10, and wherein the heteroaryl is
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, furanyl,
thiophenyl, oxazolyl, isoxazolyl or thiazolyl.

14. A compound of formula (Int-I) ##STR00237## wherein A1,
A2, A3, A4, G1, L, R1, R2, Y1,
Y2, Y3 and Y4 are as defined for a compound of formula (I)
according to claim 1 and XB is a leaving group, or XB is cyano,
formyl, CH═N--OH or acetyl; or a salt or N-oxide thereof; or a
compound of formula (Int-II) ##STR00238## wherein A1, A2,
A3, A4, G1, L, R1, R2, Y1, Y2, Y3
and Y4 are as defined for a compound of formula (I) according to
claim 1 and XC is CH2-halogen, CH═C(R3)R4, or
CH2C(OH)(R3)R4 wherein R3 and R4 are as defined
for a compound of formula (I) according to claim 1; or a salt or N-oxide
thereof.

15. A method of combating and/or controlling an invertebrate animal pest
which comprises applying to the pest, to a locus of the pest, or to a
plant susceptible to attack by the pest a pesticidally effective amount
of a compound of formula (I) as defined in claim 1.

16. A composition comprising a pesticidally effective amount of a
compound of formula (I) as defined in claim 1 optionally comprising an
additional pesticidally active ingredient.

Description:

[0001] The present invention relates to certain benzamide isoxazolines, to
processes and intermediates for preparing them, to insecticidal,
acaricidal, nematicidal and molluscicidal compositions comprising them
and to methods of using them to combat and control insect, acarine,
nematode and mollusc pests.

wherein A1, A2, A3 and A4 are independently of one
another C--H, C--R5, or nitrogen; G1 is oxygen or sulfur; L is
a single bond or C1-C8alkylene; R1 is hydrogen,
C1-C8alkyl, C1-C8alkylcarbonyl-,
C1-C8alkoxy, C1-C8alkoxy-C1-C8alkyl, or
C1-C8alkoxycarbonyl-; R2 is hydrogen,
C1-C8haloalkyl or C1-C8alkyl; R3 is
C1-C8haloalkyl; R4 is aryl or aryl substituted by one to
three R6, or R4 is heterocyclyl or heterocyclyl substituted by
one to three R6; each R5 is independently halogen, cyano,
nitro, C1-C8alkyl, C3-C8cycloalkyl,
C1-C8haloalkyl, C2-C8alkenyl,
C2-C8haloalkenyl, C2-C8alkynyl,
C2-C8haloalkynyl, C1-C8alkoxy,
C1-C8haloalkoxy, C1-C8alkoxycarbonyl-, or two R5
on adjacent carbon atoms together form a --CH═CH--CH═CH-- bridge
or a --N═CH--CH═CH-- bridge; each R6 is independently
halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl,
C1-C8alkoxy, or C1-C8-haloalkoxy;

Y1 is CR7R8 or C═O;

[0005] Y2, Y3 and Y4 are independently CR7R8,
C═O, N--R9, O, S, SO or SO2; wherein at least two adjacent
ring atoms in the ring formed by Y1, Y2, Y3 and Y4
are heteroatoms; each R7 and R8 is independently hydrogen,
halogen, C1-C8alkyl, or C1-C8haloalkyl; each R9
is independently hydrogen, cyano, cyano-C1-C8 alkyl,
C1-C8 alkyl, C1-C8 haloalkyl,
C3-C8cycloalkyl, C3-C8cycloalkyl where one carbon
atom is replaced by O, S, S(O) or SO2, or C3-C8
cycloalkyl-C1-C8 alkyl, C3-C8
cycloalkyl-C1-C8 alkyl where one carbon atom in the cycloalkyl
group is replaced by O, S, S(O) or SO2, or
C3-C8cycloalkyl-C1-C8haloalkyl, C1-C8
hydroxyalkyl, C1-C8 alkoxy-C1-C8 alkyl,
C2-C8alkenyl, C2-C8 haloalkenyl, C2-C8
alkynyl, C2-C8haloalkynyl, phenyl, phenyl substituted by one to
three R10, phenyl-C1-C4alkyl, phenyl-C1-C4alkyl
wherein the phenyl moiety is substituted by one to three R10, 5-6
membered heteroaryl-C1-C4alkyl or 5-6 membered
heteroaryl-C1-C4alkyl wherein the heteroaryl moiety is
substituted by one to three R10, or C1-C4
alkyl-(C1-C4 alkyl-O--N═)C--CH2--; each R10 is
independently halogen, cyano, nitro, C1-C8 alkyl,
C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8
haloalkoxy; or a salt or N-oxide thereof.

[0006] The compounds of formula (I) may exist in different geometric or
optical isomers or tautomeric forms. This invention covers all such
isomers and tautomers and mixtures thereof in all proportions as well as
isotopic forms such as deuterated compounds.

[0007] The compounds of the invention may contain one or more asymmetric
carbon atoms, for example, in the --CR3R4-- group or at the
LR2Y1Y4 carbon and may exist as enantiomers (or as pairs
of diastereoisomers) or as mixtures of such. Further, where any Y group
is SO, the compounds of the invention are sulfoxides, which can also
exist in two enantiomeric forms.

[0008] Each alkyl moiety either alone or as part of a larger group (such
as alkoxy, alkylcarbonyl, or alkoxycarbonyl) is a straight or branched
chain and is, for example, methyl, ethyl, n-propyl, prop-2-yl, n-butyl,
but-2-yl, 2-methyl-prop-1-yl or 2-methyl-prop-2-yl. The alkyl groups are
preferably C1-C6 alkyl groups, more preferably C1-C4
and most preferably C1-C3 alkyl groups.

[0009] Alkenyl moieties can be in the form of straight or branched chains,
and the alkenyl moieties, where appropriate, can be of either the (E)- or
O-configuration. Examples are vinyl and allyl. The alkenyl groups are
preferably C2-C6, more preferably C2-C4 and most
preferably C2-C3 alkenyl groups.

[0010] Alkynyl moieties can be in the form of straight or branched chains.
Examples are ethynyl and propargyl. The alkynyl groups are preferably
C2-C6, more preferably C2-C4 and most preferably
C2-C3 alkynyl groups.

[0011] Halogen is fluorine, chlorine, bromine or iodine.

[0012] Haloalkyl groups (either alone or as part of a larger group, such
as haloalkoxy) are alkyl groups which are substituted by one or more of
the same or different halogen atoms and are, for example,
trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoro-ethyl or
2,2-difluoro-ethyl.

[0013] Haloalkenyl groups are alkenyl groups, respectively, which are
substituted with one or more of the same or different halogen atoms and
are, for example, 2,2-difluorovinyl or 1,2-dichloro-2-fluoro-vinyl.

[0014] Haloalkynyl groups are alkynyl groups, respectively, which are
substituted with one or more of the same or different halogen atoms and
are, for example, 1-chloro-prop-2-ynyl.

[0015] In the context of the present specification the term "aryl" refers
to a ring system which may be mono-, bi- or tricyclic. Examples of such
rings include phenyl, naphthalenyl, anthracenyl, indenyl or
phenanthrenyl. A preferred aryl group is phenyl.

[0016] The term "heteroaryl" refers to an aromatic ring system containing
at least one heteroatom and consisting either of a single ring or of two
or more fused rings. Preferably, single rings will contain up to three
heteroatoms and bicyclic systems up to four heteroatoms which will
preferably be chosen from nitrogen, oxygen and sulfur. Examples of (5-6
membered) monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,
furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,
isothiazolyl, and thiadiazolyl. Examples of bicyclic groups include
quinolinyl, cinnolinyl, quinoxalinyl, benzimidazolyl, benzothiophenyl,
and benzothiadiazolyl. Monocyclic heteroaryl groups are preferred,
preferably monocyclic rings containing 1 to 3 heterotoms selected from O,
N or S, e.g. pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,
furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, preferably pyridyl,
pyrazolyl, furanyl, thiophenyl, thiazolyl, pyridyl being most preferred.

[0017] The term "heterocyclyl" is defined to include heteroaryl and in
addition their unsaturated or partially unsaturated analogues.

[0025] Preferably L is a single bond or C1-C4alkylene. More
preferably L is a single bond or CH2, most preferably a single bond.

[0026] Preferably R1 is hydrogen, methyl, ethyl, methylcarbonyl-, or
methoxycarbonyl-, more preferably hydrogen, methyl or ethyl, even more
preferably hydrogen or methyl, most preferably hydrogen.

[0027] Preferably R2 is hydrogen or methyl, most preferably hydrogen.

[0028] Preferably R3 is chlorodifluoromethyl or trifluoromethyl, most
preferably trifluoromethyl.

[0029] Preferably R4 is aryl or aryl substituted by one to three
R6, more preferably R4 is phenyl or phenyl substituted by one
to three R6, even more preferably R4 is phenyl substituted by
one to three R6, more preferably R4 is
3,5-bis-(trifluoromethyl)-phenyl, 3-chloro-5-trifluoromethyl-phenyl,
3-bromo-5-trifluoromethyl-phenyl, 3,5-dibromo-phenyl,
3,5-dichloro-phenyl, 3,4-dichloro-phenyl, 3-trifluoromethyl-phenyl,
4-bromo-3,5-dichlorophenyl, 4-fluoro-3,5-dichlorophenyl or
3,4,5-trichloro-phenyl, yet even more preferably R4 is
3,5-dibromo-phenyl, 3,5-dichloro-phenyl,
3,5-bis-(trifluoromethyl)-phenyl, 4-bromo-3,5-dichlorophenyl, or
3,4,5-trichloro-phenyl, most preferably R4 is 3,5-dichlorophenyl.

[0037] In one embodiment Y2 or Y4 is C═O. According to this
embodiment the grouping --Y2--Y3--Y4-- is preferably
selected from --C(═O)--N(--R9)--N(--R9)--,
--C(═O)--N(--R9)--O--, --C(═O)--N(--R9)--S--,
--C(═O)--O--N(--R9)--, --C(═O)--S--N(--R9)--,
--N(--R9)--N(--R9)--C(═O)--,
--N(--R9)--O--C(═O)--, --O--N(--R9)--C(═O)-- and
--S--N(--R9)--C(═O). More preferably the grouping
--Y2--Y3--Y4-- is selected from
--O--N(--R9)--C(═O)-- and --C(═O)--N(--R9)--O--.

[0039] In one embodiment Y2 and Y4 are independently N--R9,
O, S, SO or SO2. According to this embodiement the grouping
--Y2--Y3--Y4-- is preferably selected from
--N(--R9)--SO--N(--R9)--,
--N(--R9)--SO2--N(--R9)--, --N(--R9)--SO2--O--,
--O--N(--R9)--SO--, --O--N(--R9)--SO2--,
--N(--R9)--SO--N(--R9)--, --N(--R9)--SO--O--,
--N(--R9)--SO2--N(--R9)--, --N(--R9)--SO2--O--,
--SO--N(--R9)--N(--R9)--,
--SO2--N(--R9)--N(--R9)-- and
--SO2--N(--R9)--O--. More preferably the grouping
Y2--Y3--Y4-- is selected from
--N(--R9)--SO2--O--, --O--SO2--O--,
--N(--R9)--SO2--N(--R9)--, --O--SO2--N(--R9)--
and --N(--R9)--SO2--O--. More preferably the grouping
--Y2--Y3--Y4-- is selected from
--N(--R9)--SO2--O--, --O--SO2--O--,
--N(--R9)--SO2--N(--R9)--, and
--O--SO2--N(--R9)--.

[0040] In one embodiment Y1 is CR7R8 or C═O; Y2
and Y3 are independently CR7R8, C═O, N--R9, O, S,
SO or SO2; Y4 is CR7R8, C═O, SO or SO2.
Preferably Y2 and Y3 are independently N--R9, O, S, SO,
SO2. Preferably Y2 and Y3 are independently N--R9, O
or S. Preferably Y2 is O or S. More preferably Y2 is O.
Preferably Y3 is N--R9. Preferably Y4 is C═O.
Preferably Y3 is N--R9 and Y4 is C═O. Preferably
Y2 is O, Y3 is N--R9 and Y4 is C═O.

[0041] Preferably Y1 is CR7R8, Y2 is O, Y3 is
N--R9 and Y4 is C═O.

[0042] In one embodiment Y1 is CR7R8, Y2 and Y3
are independently N--R9, O, S, SO or SO2 and Y4 is
CR7R8, C═O, SO or SO2.

[0043] In one embodiment Y1 is CR7R8, Y2 is
N--R9, O, S, SO or SO2, Y3 is N--R9, and Y4 is
CR7R8, C═O, SO or SO2, preferably Y1 is
CR7R8, Y2 is O or S, Y3 is N--R9, and Y4 is
C═O, preferably Y1 is CR7R8, Y2 is O, Y3 is
N--R9, and Y4 is C═O.

[0044] In one embodiment Y1 is CR7R8, Y2 is
N--R9, O, S, SO or SO2, Y3 is O or S, Y4 is C═O,
SO, or SO2.

[0045] In one embodiment Y1 is C═O, Y2 is N--R9 or O,
Y3 is N--R9, Y4 is C═O, SO, or SO2.

[0046] In one embodiment Y1 is CR7R8, C═O, Y2 is
CR7R8, C═O, Y3 is N--R9, O or S, and Y4 is
SO, or SO2.

[0047] Preferably Y4 is CR7R8 or C═O when L is a bond,
e.g. the grouping --Y2--Y3--Y4-- is
--S--C(R7)(R8)--, --SO--O--C(R7)(R8)-- or
--O--N(--R9)--C(═O)--, more preferably
--SO--O--C(R7)(R8)-- or --O--N(--R9)--C(═O)--.

[0048] Preferably when Y4 is a heteroatom, L is
C1-C4alkylene.

[0049] Preferably when Y4 is NR9, L is C1-C4alkylene,
in which case Y3 is preferably NR9, O, S, SO or SO2.

[0050] Preferably when Y4 is O, L is C1-C4alkylene, in
which case Y3 is preferably NR9.

[0051] In all embodiments at least two adjacent ring atoms in the ring
formed by Y1, Y2, Y3 and Y4 are heteroatoms.
Preferably the ring formed by Y1, Y2, Y3 and Y4 does
not contain two adjacent oxygen atoms. In some cases there may be no more
than one oxygen ring atom in the ring formed by Y1, Y2, Y3
and Y4. Embodiments providing Y1, Y2, Y3, Y4
values may be combined with any of the values, including preferred
values, of A1, A2, A3, A4, G1, L, R1,
R2, R3, R4, R5, R6, R7, R8, R9
and R10.

[0052] Preferably each R7 is independently hydrogen, or
C1-C8alkyl, most preferably hydrogen.

[0053] Preferably each R8 is independently hydrogen, or
C1-C8alkyl, most preferably hydrogen.

[0054] Preferably R7 and R8 are both hydrogen.

[0055] Preferably each R9 is independently hydrogen,
cyano-C1-C8alkyl, C1-C8alkyl,
C3-C8cycloalkyl, C3-C8cycloalkyl where one carbon
atom in the cycloalkyl group is replaced by O, S, S(O) or SO2, or
C3-C8cycloalkyl-C1-C8alkyl,
C3-C8cycloalkyl-C1-C8alkyl where one carbon atom in
the cycloalkyl group is replaced by O, S, S(O) or SO2, or
C1-C8haloalkyl, C1-C8hydroxyalkyl,
C1-C8hydroxyalkyl, C2-C8alkenyl,
C2-C8alkynyl, phenyl-C1-C4alkyl or
phenyl-C1-C4alkyl wherein the phenyl moiety is substituted by
one to three R10, 5-6 membered heteoaryl-C1-C4alkyl or 5-6
membered heteroaryl-C1-C4alkyl wherein the heteroaryl moiety is
substituted by one to three R10; more preferably each R9 is
independently hydrogen, cyano-C1-C8alkyl-,
C1-C8alkyl, C3-C8cycloalkyl,
C3-C8cycloalkyl where one carbon atom in the cycloalkyl group
is replaced by O, S, S(O) or SO2, or C1-C8haloalkyl,
C1-C8 hydroxyalkyl, C2-C8 alkenyl, C2-C8
alkynyl, phenyl-C1-C4 alkyl or phenyl-C1-C4alkyl
wherein the phenyl moiety is substituted by one to three R10, 5-6
membered heteroaryl-C1-C4alkyl or 5-6 membered
heteroaryl-C1-C4alkyl wherein the heteroaryl moiety is
substituted by one to three R10; even more preferably each R9
is independently hydrogen, cyano-C1-C6 alkyl,
C1-C6alkyl, C3-C6 cycloalkyl,
C3-C6cycloalkyl where one carbon atom in the cycloalkyl group
is replaced by O, S, S(O) or SO2, or C1-C6halo alkyl,
C1-C6hydroxyalkyl, C1-C6 alkoxy-C1-C6
alkyl, C2-C6alkenyl, C2-C6 alkynyl,
phenyl-CH2-alkyl or phenyl-CH2-- wherein the phenyl moiety is
substituted by one to three R10, furanyl or furanyl substituted by
one to three R10, triazolyl or triazolyl optionally substituted by
one to three R10; yet even more preferably each R9 is
independently hydrogen, C1-C4 alkyl, C3-C6
cycloalkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl,
C1-C4alkoxy-C1-C4alkyl, phenyl-CH2-alkyl- or
phenyl-CH2-- wherein the phenyl moiety is substituted by one to
three R10, furanyl or furanyl substituted by one to three R10,
thietanyl, oxetanyl, oxo-thietanyl, or dioxo-thietanyl; yet even more
preferably each R9 is independently methyl, ethyl, cyclopropyl,
cyclobutyl, oxetanyl, thietanyl, trifluoroethyl, difluoroethyl, allyl,
propargyl, cyanomethyl, benzyl, benzyl substituted by one to three
R10, or pyridine-methyl- or pyridine-methyl-substituted by one to
three R10. Ethyl and trifluoroethyl are particularly preferred.
Heteroaryl preferably refers to pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, pyrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl or
thiazolyl, more preferably pyridyl, pyrazolyl, furanyl, thiophenyl or
thiazolyl, most preferably pyridyl.

[0057] In one embodiment of compounds of formula (I) A1, A2,
A3 and A4 are independently of one another C--H, C--R5, or
nitrogen;

G1 is oxygen or sulfur; L is a single bond or
C1-C8alkylene; R1 is hydrogen, C1-C8alkyl,
C1-C8alkylcarbonyl-, or C1-C8alkoxycarbonyl-; R2
is hydrogen, or C1-C8alkyl; R3 is
C1-C8haloalkyl; R4 is aryl, aryl substituted by one to
three R6, or R4 is heterocyclyl, or heterocyclyl substituted by
one to three R6; each R5 is independently halogen, cyano,
nitro, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8
haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl,
C2-C8alkynyl, C2-C8haloalkynyl,
C1-C8alkoxy, C1-C8haloalkoxy,
C1-C8alkoxycarbonyl-, or two R5 on adjacent carbon atoms
together form a --CH═CH--CH═CH-- bridge; each R6 is
independently halogen, cyano, nitro, C1-C8alkyl,
C1-C8haloalkyl, C1-C8alkoxy, or C1-C8
haloalkoxy;

[0059] wherein at least two adjacent ring atoms in the ring formed by
Y1, Y2, Y3 and Y4 are heteroatoms; each R7 and
R8 is independently hydrogen, halogen, C1-C8alkyl, or
C1-C8haloalkyl; each R9 is independently hydrogen, cyano,
cyano-C1-C8alkyl, C1-C8 alkyl, C1-C8
haloalkyl, C3-C8cycloalkyl, C3-C8cycloalkyl where one
carbon atom is replaced by O, S, S(O) or SO2, C3-C8
cycloalkyl-C1-C8 alkyl, C3-C8
cycloalkyl-C1-C8 alkyl where one carbon atom in the cycloalkyl
group is replaced by O, S, S(O) or SO2,
C3-C8cycloalkyl-C1-C8haloalkyl, C1-C8
hydroxyalkyl, C1-C8 alkoxy-C1-C8alkyl,
C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8
alkynyl, C2-C8haloalkynyl, phenyl-C1-C4alkyl,
phenyl-C1-C4alkyl wherein the phenyl moiety is substituted by
one to three R10, or each R9 is independently 5-6 membered
heteroaryl-C1-C4alkyl or 5-6 membered
heteroaryl-C1-C4alkyl wherein the heteroaryl moiety is
substituted by one to three R10; each R10 is independently
halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl,
C1-C8alkoxy, or C1-C8haloalkoxy, or a salt of N-oxide
thereof. In this embodiment each R9 is preferably independently
hydrogen, cyano-C1-C8 cycloalkyl, C3-C8
cycloalkyl-C1-C8alkyl, C1-C8 haloalkyl,
C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl,
C2-C8 alkenyl, C2-C8 alkynyl,
phenyl-C1-C4alkyl or phenyl-C1-C4alkyl wherein the
phenyl moiety is substituted by one to three R10, or each R9 is
independently heteoaryl-C1-C4alkyl or
heteroaryl-C1-C4alkyl wherein the heteroaryl moiety is
substituted by one to three R10, even more preferably each R9
is independently hydrogen, cyano-C1-C8alkyl,
C1-C8alkyl, C3-C8cycloalkyl,
C1-C8haloalkyl, C1-C8alkoxyalkyl,
C2-C8alkenyl, C2-C8alkynyl,
phenyl-C1-C4alkyl- or phenyl-C1-C4alkyl wherein the
phenyl moiety is substituted by one to three R10, or each R9 is
independently heteroaryl-C1-C4alkyl or
heteroaryl-C1-C4alkyl wherein the heteroaryl moiety is
substituted by one to three R10, yet even more preferably each
R9 is independently hydrogen, methyl, ethyl, cyclopropyl,
cyclobutyl, oxetanyl, thietanyl, trifluoroethyl, difluoroethyl, allyl,
propargyl, cyanomethyl, benzyl, benzyl substituted by one to three
R10, or each R9 is independently pyridine-methyl- or
pyridine-methyl-substituted by one to three R10. In this embodiment,
the preferred values of Y1, Y2, Y3, Y4, G1,
R1, R2, R3, R4, R5, R6, R7, R8
and R10 are as defined above.

[0060] A preferred embodiment provides compounds of formula (Ia.A) wherein
A1 is C--R5, A2, A3, and A4 are C--H, R4 is
3,5-dichloro-phenyl, L is a bond, and G1, R1, R2, R3,
R5, Y1, Y2, Y3 and Y4 are as defined for a
compound of formula (I); or a salt or N-oxide thereof.

[0061] A preferred embodiment provides compounds of formula (Ia.B) wherein
A1 is C-Me, A2, A3, and A4 are C--H, R4 is
3,5-dichloro-phenyl, L is a bond, and G1, R1, R2, R3,
Y1, Y2, Y3 and Y4 are as defined for a compound of
formula (I); or a salt or N-oxide thereof.

[0062] A preferred embodiment provides compounds of formula (Ia.C)

##STR00003##

wherein R2 is hydrogen or C1-C4 alkyl; R3 is
C1-C4 haloalkyl; R4 is phenyl, or phenyl substituted by
one to three R6; R5 is halogen, nitro, C1-C4alkyl,
C3-C4cycloalkyl, C2-C4alkenyl or
C1-C4haloalkyl; A3 and A4 are independently C--H or
N; L is a bond or methylene; R1, R6, Y1, Y2, Y3,
and Y4 are as defined for formula (I); wherein at least two adjacent
ring atoms in the ring formed by Y1, Y2, Y3 and Y4
are heteroatoms; or a salt or N-oxide thereof. Preferred values of
Y1, Y2, Y3, Y4, A3, A4, R1, R2,
R3, R4, R5 and R6 are as defined for formula I.

[0063] A preferred embodiment provides compounds of formula (Ia.D)

##STR00004##

wherein R5, Y1, Y2, Y3, Y4 and their preferred
values are as defined for formula (I); wherein at least two adjacent ring
atoms in the ring formed by Y1, Y2, Y3 and Y4 are
heteroatoms; or a salt or N-oxide thereof.

[0064] A further preferred embodiment provides compounds of formula (Ia.E)

##STR00005##

wherein

[0065] A1, A2, A3, A4, R3, R4 and R9
and their preferred values are as defined for a compound of formula (I);
or a salt or N-oxide thereof. Certain intermediates are novel and as such
form a further aspect of the invention.

[0066] A further preferred embodiment provides compounds of formula (Ia.F)

##STR00006##

wherein

[0067] A1, A2, A3, A4, R3 and R4 and their
preferred values are as defined for a compound of formula (I); or a salt
or N-oxide thereof.

[0068] Certain intermediates are novel and as such form a further aspect
of the invention. One group of novel intermediates are compounds of
formula (Int-I)

##STR00007##

[0069] wherein A1, A2, A3, A4, G1, L, R1,
R2, Y1, Y2, Y3 and Y4 are as defined for a
compound of formula (I) and XB is a leaving group, for example a
halogen, such as bromo, or XB is cyano, formyl, CH═N--OH or
acetyl; or a salt or N-oxide thereof. The preferences for A1,
A2, A3, A4, G1, L, R1, R2, Y1,
Y2, Y3 and Y4 are the same as the preferences set out for
the corresponding substituents of a compound of formula (I). For example,
the preferences for A1, A2, A3, A4, G1, L,
R1, R2, Y1, Y2, Y3 and Y4 may be the same
as for formula (Ia.A), (Ia.B), (Ia.C), (Ia.D), (Ia.E) or (Ia.F).

[0070] Another group of novel intermediates are compounds of formula
(Int-II)

##STR00008##

[0071] wherein A1, A2, A3, A4, G1, L, R1,
R2, Y1, Y2, Y3 and Y4 are as defined for a
compound of formula (I); XC is CH2-halogen, wherein halogen is
e.g. bromo or chloro, CH═C(R3)R4 or
CH2C(OH)(R3)R4 wherein R3 and R4 are as defined
for a compound of formula (I); or a salt or N-oxide thereof. The
preferences for A1, A2, A3, A4, G1, L, R1,
R2, Y1, Y2, Y3 and Y4 are the same as the
preferences set out for the corresponding substituents of a compound of
formula (I). For example, the preferences for A1, A2, A3,
A4, G1, L, R1, R2, Y1, Y2, Y3 and
Y4 may be the same as for formula (Ia.A), (Ia.B), (Ia.C), (Ia.D),
(Ia.E) or (Ia.F).

[0072] The compounds in Table 1 to Table 2 below illustrate the compounds
of the invention.

[0073] Compounds of formula I include at least one chiral centre and may
exist as compounds of formula I* or compounds of formula I**. Compounds
I* and I** are enantiomers if there is no other chiral center or epimers
otherwise.

##STR00011##

Generally compounds of formula I** are more biologically active than
compounds of formula I*. The invention includes mixtures of compounds I*
and I** in any ratio e.g. in a molar ratio of 1:99 to 99:1, e.g. 10:1 to
1:10, e.g. a substantially 50:50 molar ratio. In an enantiomerically (or
epimerically) enriched mixture of formula I**, the molar proportion of
compound I** compared to the total amount of both enantiomers is for
example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90,
95, 96, 97, 98, or at least 99%. Likewise, in enantiomerically (or
epimerically) enriched mixture of formula I*, the molar proportion of the
compound of formula I* compared to the total amount of both enantiomers
(or epimerically) is for example greater than 50%, e.g. at least 55, 60,
65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%. Enantiomerically
(or epimerically) enriched mixtures of formula I** are preferred.

[0074] The compounds of the invention may be made by a variety of methods
as shown in Schemes 1 and 2.

##STR00012##

[0075] 1) Compounds of formula (I) wherein G1 is oxygen, can be
prepared by reacting a compound of formula (II) wherein G1 is oxygen
and R is OH, C1-C6alkoxy or Cl, F or Br, with an amine of
formula (III) as shown in Scheme 1. When R is OH such reactions are
usually carried out in the presence of a coupling reagent, such as
N,N'-dicyclohexylcarbodiimide ("DCC"),
1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride ("EDC") or
bis(2-oxo-3-oxazolidinyl)phosphonic chloride ("BOP--C1"), in the presence
of a base, and optionally in the presence of a nucleophilic catalyst,
such as hydroxybenzotriazole ("HOBT"). When R is Cl, such reactions are
usually carried out in the presence of a base, and optionally in the
presence of a nucleophilic catalyst. Alternatively, it is possible to
conduct the reaction in a biphasic system comprising an organic solvent,
preferably ethyl acetate, and an aqueous solvent, preferably a solution
of sodium hydrogen carbonate. When R is C1-C6alkoxy it is
sometimes possible to convert the ester directly to the amide by heating
the ester and amine together in a thermal process. Suitable bases include
pyridine, triethylamine, 4-(dimethylamino)-pyridine ("DMAP") or
diisopropylethylamine (Hunig's base). Preferred solvents are
N,N-dimethylacetamide, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,
ethyl acetate and toluene. The reaction is carried out at a temperature
of from 0° C. to 100° C., preferably from 15° C. to
30° C., in particular at ambient temperature. Amines of formula
(III) are either known in the literature or can be prepared using methods
known to a person skilled in the art. Some of these methods are described
in the preparation Examples.

[0076] 2) Acid halides of formula (II), wherein G1 is oxygen and R is
Cl, F or Br, may be made from carboxylic acids of formula (II), wherein
G1 is oxygen and R is OH, under standard conditions, as described
for example in WO09080250.

[0077] 3) Carboxylic acids of formula (II), wherein G1 is oxygen and
R is OH, may be formed from esters of formula (II), wherein G1 is
oxygen and R is C1-C6alkoxy as described for example in
WO09080250.

[0078] 4) Compounds of formula (I) wherein G1 is oxygen, can be
prepared by reacting a compound of formula (IV) wherein XB is a
leaving group, for example a halogen, such as bromo, with carbon monoxide
and an amine of formula (III), in the presence of a catalyst, such as
palladium(II) acetate or bis(triphenylphosphine)palladium(II) dichloride,
optionally in the presence of a ligand, such as triphenylphosphine, and a
base, such as sodium carbonate, pyridine, triethylamine,
4-(dimethylamino)-pyridine ("DMAP") or diisopropyl-ethylamine (Hunig's
base), in a solvent, such as water, N,N-dimethylformamide or
tetrahydrofuran. The reaction is carried out at a temperature of from
50° C. to 200° C., preferably from 100° C. to
150° C. The reaction is carried out at a pressure of from 50 to
200 bar, preferably from 100 to 150 bar.

[0079] 5) Compounds of formula (IV) wherein XB is a leaving group,
for example a halogen, such as bromo, can be made by a various of
methods, for example as described in WO09080250.

[0080] 6) Compounds of formula (I), wherein G1 is sulfur, may be made
by treatment of a compound of formula (II), wherein G1 is oxygen and
R is OH, C1-C6alkoxy or Cl, F or Br, with a thio-transfer
reagent such as Lawesson's reagent or phosphorus pentasulfide prior to
elaborating to compounds of formula (I), as described under 1).

##STR00013##

[0081] 7) Alternatively, compounds of formula (I) wherein G1 is
oxygen, can be prepared by various methods from an intermediate of
formula (V) as shown in Scheme 2 wherein G1 is oxygen and XB is
a leaving group, for example a halogen, such as bromo, or XB is
cyano, formyl or acetyl according to similar methods to those described
in WO09080250. An intermediate of formula (V) can be prepared for example
from an intermediate of formula (VI) as described in the same reference.

##STR00014##

[0082] 8) Alternatively, compounds of formula (I) wherein G1 is
oxygen, can be prepared by various methods from an intermediate of
formula (VII) as shown in Scheme 3 wherein G1 is oxygen and XC
is CH═C(R3)R4, or CH2C(OH)(R3)R4 wherein
R3 and R4 are as defined for a compound of formula (I)
according to similar methods to those described in WO09080250.

[0083] 9) Compounds of formula (VII) wherein G1 is oxygen and XC
is CH═C(R3)R4, or CH2C(OH)(R3)R4 can be
prepared from a compound of formula (Va) wherein G1 is oxygen or
from a compound of formula (VII) wherein G1 is oxygen and XC is
CH2-halogen using similar methods to those described in WO09080250.

[0084] 10) Compounds of formula (VII) wherein G1 is oxygen and
XC is CH2-halogen, such as bromo or chloro, can be prepared by
reacting a methyl ketone of formula (Va) wherein G1 is oxygen, with
a halogenating agent, such as bromine or chlorine, in a solvent, such as
acetic acid, at a temperature of from 0° C. to 50° C.,
preferably from ambient temperature to 40° C.

[0085] 11) Compounds of formula (III) are either known compounds or can be
be prepared by known methods to the person skilled in the art. Examples
of such methods can be found in the Examples below.

[0086] The compounds of formula (I) can be used to combat and control
infestations of insect pests such as Lepidoptera, Diptera, Hemiptera,
Thysanoptera, Orthoptera, Dictyoptera, Coleoptera, Siphonaptera,
Hymenoptera and Isoptera and also other invertebrate pests, for example,
acarine, nematode and mollusc pests. Insects, acarines, nematodes and
molluscs are hereinafter collectively referred to as pests. The pests
which may be combated and controlled by the use of the invention
compounds include those pests associated with agriculture (which term
includes the growing of crops for food and fiber products), horticulture
and animal husbandry, companion animals, forestry and the storage of
products of vegetable origin (such as fruit, grain and timber); those
pests associated with the damage of man-made structures and the
transmission of diseases of man and animals; and also nuisance pests
(such as flies).

[0087] The compounds of the invention may be used for example on turf,
ornamentals, such as flowers, shrubs, broad-leaved trees or evergreens,
for example conifers, as well as for tree injection, pest management and
the like.

[0089] The invention therefore provides a method of combating and/or
controlling an animal pest, e.g. an invertebrate animal pest, which
comprises applying to the pest, to a locus of the pest, or to a plant
susceptible to attack by the pest a pesticidally effective amount of a
compound of formula (I). In particular, the invention provides a method
of combating and/or controlling insects, acarines, nematodes or molluscs
which comprises applying an insecticidally, acaricidally, nematicidally
or molluscicidally effective amount of a compound of formula (I), or a
composition containing a compound of formula (I), to a pest, a locus of
pest, preferably a plant, or to a plant susceptible to attack by a pest,
The compounds of formula (I) are preferably used against insects,
acarines or nematodes.

[0090] The term "plant" as used herein includes seedlings, bushes and
trees.

[0091] Crops are to be understood as also including those crops which have
been rendered tolerant to herbicides or classes of herbicides (e.g. ALS-,
GS-, EPSPS-, PPO- and HPPD-inhibitors) by conventional methods of
breeding or by genetic engineering. An example of a crop that has been
rendered tolerant to imidazolinones, e.g. imazamox, by conventional
methods of breeding is Clearfield® summer rape (canola). Examples of
crops that have been rendered tolerant to herbicides by genetic
engineering methods include e.g. glyphosate- and glufosinate-resistant
maize varieties commercially available under the trade names
RoundupReady® and LibertyLink®.

[0092] Crops are also to be understood as being those which have been
rendered resistant to harmful insects by genetic engineering methods, for
example Bt maize (resistant to European corn borer), Bt cotton (resistant
to cotton boll weevil) and also Bt potatoes (resistant to Colorado
beetle). Examples of Bt maize are the Bt 176 maize hybrids of NK®
(Syngenta Seeds). Examples of transgenic plants comprising one or more
genes that code for an insecticidal resistance and express one or more
toxins are KnockOut® (maize), Yield Gard® (maize),
NuCOTIN33B® (cotton), Bollgard® (cotton), NewLeaf®
(potatoes), NatureGard® and Protexcta®.

[0093] Plant crops or seed material thereof can be both resistant to
herbicides and, at the same time, resistant to insect feeding ("stacked"
transgenic events). For example, seed can have the ability to express an
insecticidal Cry3 protein while at the same time being tolerant to
glyphosate.

[0094] Crops are also to be understood as being those which are obtained
by conventional methods of breeding or genetic engineering and contain
so-called output traits (e.g. improved storage stability, higher
nutritional value and improved flavor).

[0095] In order to apply a compound of formula (I) as an insecticide,
acaricide, nematicide or molluscicide to a pest, a locus of pest, or to a
plant susceptible to attack by a pest, a compound of formula (I) is
usually formulated into a composition which includes, in addition to the
compound of formula (I), a suitable inert diluent or carrier and,
optionally, a surface active agent (SFA). SFAs are chemicals which are
able to modify the properties of an interface (for example, liquid/solid,
liquid/air or liquid/liquid interfaces) by lowering the interfacial
tension and thereby leading to changes in other properties (for example
dispersion, emulsification and wetting). It is preferred that all
compositions (both solid and liquid formulations) comprise, by weight,
0.0001 to 95%, more preferably 1 to 85%, for example 5 to 60%, of a
compound of formula (I). The composition is generally used for the
control of pests such that a compound of formula (I) is applied at a rate
of from 0.1 g to 10 kg per hectare, preferably from 1 g to 6 kg per
hectare, more preferably from 1 g to lkg per hectare.

[0096] When used in a seed dressing, a compound of formula (I) is used at
a rate of 0.0001 g to 10 g (for example 0.001 g or 0.05 g), preferably
0.005 g to 10 g, more preferably 0.005 g to 4 g, per kilogram of seed.

[0097] In another aspect the present invention provides a composition
comprising a pesticidally effective amount of a compound of formula (I),
in particular an insecticidal, acaricidal, nematicidal or molluscicidal
composition comprising an insecticidally, acaricidally, nematicidally or
molluscicidally effective amount of a compound of formula (I) and a
suitable carrier or diluent therefor. The composition is preferably an
insecticidal, acaricidal, nematicidal or molluscicidal composition.

[0100] Soluble powders (SP) may be prepared by mixing a compound of
formula (I) with one or more water-soluble inorganic salts (such as
sodium bicarbonate, sodium carbonate or magnesium sulfate) or one or more
water-soluble organic solids (such as a polysaccharide) and, optionally,
one or more wetting agents, one or more dispersing agents or a mixture of
said agents to improve water dispersibility/solubility. The mixture is
then ground to a fine powder. Similar compositions may also be granulated
to form water soluble granules (SG).

[0101] Wettable powders (WP) may be prepared by mixing a compound of
formula (I) with one or more solid diluents or carriers, one or more
wetting agents and, preferably, one or more dispersing agents and,
optionally, one or more suspending agents to facilitate the dispersion in
liquids. The mixture is then ground to a fine powder. Similar
compositions may also be granulated to form water dispersible granules
(WG).

[0102] Granules (GR) may be formed either by granulating a mixture of a
compound of formula (I) and one or more powdered solid diluents or
carriers, or from pre-formed blank granules by absorbing a compound of
formula (I) (or a solution thereof, in a suitable agent) in a porous
granular material (such as pumice, attapulgite clays, fuller's earth,
kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing a
compound of formula (I) (or a solution thereof, in a suitable agent) on
to a hard core material (such as sands, silicates, mineral carbonates,
sulfates or phosphates) and drying if necessary. Agents which are
commonly used to aid absorption or adsorption include solvents (such as
aliphatic and aromatic petroleum solvents, alcohols, ethers, ketones and
esters) and sticking agents (such as polyvinyl acetates, polyvinyl
alcohols, dextrins, sugars and vegetable oils). One or more other
additives may also be included in granules (for example an emulsifying
agent, wetting agent or dispersing agent).

[0103] Dispersible Concentrates (DC) may be prepared by dissolving a
compound of formula (I) in water or an organic solvent, such as a ketone,
alcohol or glycol ether. These solutions may contain a surface active
agent (for example to improve water dilution or prevent crystallization
in a spray tank).

[0104] Emulsifiable concentrates (EC) or oil-in-water emulsions (EW) may
be prepared by dissolving a compound of formula (I) in an organic solvent
(optionally containing one or more wetting agents, one or more
emulsifying agents or a mixture of said agents). Suitable organic
solvents for use in ECs include aromatic hydrocarbons (such as
alkylbenzenes or alkylnaphthalenes, exemplified by SOLVESSO 100, SOLVESSO
150 and SOLVESSO 200; SOLVESSO is a Registered Trade Mark), ketones (such
as cyclohexanone or methylcyclohexanone) and alcohols (such as benzyl
alcohol, furfuryl alcohol or butanol), N-alkylpyrrolidones (such as
N-methylpyrrolidone or N-octylpyrrolidone), dimethyl amides of fatty
acids (such as C8-C10 fatty acid dimethylamide) and chlorinated
hydrocarbons. An EC product may spontaneously emulsify on addition to
water, to produce an emulsion with sufficient stability to allow spray
application through appropriate equipment. Preparation of an EW involves
obtaining a compound of formula (I) either as a liquid (if it is not a
liquid at room temperature, it may be melted at a reasonable temperature,
typically below 70° C.) or in solution (by dissolving it in an
appropriate solvent) and then emulsifiying the resultant liquid or
solution into water containing one or more SFAs, under high shear, to
produce an emulsion. Suitable solvents for use in EWs include vegetable
oils, chlorinated hydrocarbons (such as chlorobenzenes), aromatic
solvents (such as alkylbenzenes or alkylnaphthalenes) and other
appropriate organic solvents which have a low solubility in water.

[0105] Microemulsions (ME) may be prepared by mixing water with a blend of
one or more solvents with one or more SFAs, to produce spontaneously a
thermodynamically stable isotropic liquid formulation. A compound of
formula (I) is present initially in either the water or the solvent/SFA
blend. Suitable solvents for use in MEs include those hereinbefore
described for use in ECs or in EWs. An ME may be either an oil-in-water
or a water-in-oil system (which system is present may be determined by
conductivity measurements) and may be suitable for mixing water-soluble
and oil-soluble pesticides in the same formulation. An ME is suitable for
dilution into water, either remaining as a microemulsion or forming a
conventional oil-in-water emulsion.

[0106] Suspension concentrates (SC) may comprise aqueous or non-aqueous
suspensions of finely divided insoluble solid particles of a compound of
formula (I). SCs may be prepared by ball or bead milling the solid
compound of formula (I) in a suitable medium, optionally with one or more
dispersing agents, to produce a fine particle suspension of the compound.
One or more wetting agents may be included in the composition and a
suspending agent may be included to reduce the rate at which the
particles settle. Alternatively, a compound of formula (I) may be dry
milled and added to water, containing agents hereinbefore described, to
produce the desired end product.

[0107] Aerosol formulations comprise a compound of formula (I) and a
suitable propellant (for example n-butane). A compound of formula (I) may
also be dissolved or dispersed in a suitable medium (for example water or
a water miscible liquid, such as n-propanol) to provide compositions for
use in non-pressurized, hand-actuated spray pumps.

[0108] A compound of formula (I) may be mixed in the dry state with a
pyrotechnic mixture to form a composition suitable for generating, in an
enclosed space, a smoke containing the compound.

[0109] Capsule suspensions (CS) may be prepared in a manner similar to the
preparation of EW formulations but with an additional polymerization
stage such that an aqueous dispersion of oil droplets is obtained, in
which each oil droplet is encapsulated by a polymeric shell and contains
a compound of formula (I) and, optionally, a carrier or diluent therefor.
The polymeric shell may be produced by either an interfacial
polycondensation reaction or by a coacervation procedure. The
compositions may provide for controlled release of the compound of
formula (I) and they may be used for seed treatment. A compound of
formula (I) may also be formulated in a biodegradable polymeric matrix to
provide a slow, controlled release of the compound.

[0110] A composition may include one or more additives to improve the
biological performance of the composition (for example by improving
wetting, retention or distribution on surfaces; resistance to rain on
treated surfaces; or uptake or mobility of a compound of formula (I)).
Such additives include surface active agents, spray additives based on
oils, for example certain mineral oils or natural plant oils (such as soy
bean and rape seed oil), and blends of these with other bio-enhancing
adjuvants (ingredients which may aid or modify the action of a compound
of formula (I)).

[0111] A compound of formula (I) may also be formulated for use as a seed
treatment, for example as a powder composition, including a powder for
dry seed treatment (DS), a water soluble powder (SS) or a water
dispersible powder for slurry treatment (WS), or as a liquid composition,
including a flowable concentrate (FS), a solution (LS) or a capsule
suspension (CS). The preparations of DS, SS, WS, FS and LS compositions
are very similar to those of, respectively, DP, SP, WP, SC and DC
compositions described above. Compositions for treating seed may include
an agent for assisting the adhesion of the composition to the seed (for
example a mineral oil or a film-forming barrier).

[0112] Wetting agents, dispersing agents and emulsifying agents may be
surface SFAs of the cationic, anionic, amphoteric or non-ionic type.

[0118] A compound of formula (I) may be applied by any of the known means
of applying pesticidal compounds. For example, it may be applied,
formulated or unformulated, to the pests or to a locus of the pests (such
as a habitat of the pests, or a growing plant liable to infestation by
the pests) or to any part of the plant, including the foliage, stems,
branches or roots, to the seed before it is planted or to other media in
which plants are growing or are to be planted (such as soil surrounding
the roots, the soil generally, paddy water or hydroponic culture
systems), directly or it may be sprayed on, dusted on, applied by
dipping, applied as a cream or paste formulation, applied as a vapor or
applied through distribution or incorporation of a composition (such as a
granular composition or a composition packed in a water-soluble bag) in
soil or an aqueous environment.

[0119] A compound of formula (I) may also be injected into plants or
sprayed onto vegetation using electrodynamic spraying techniques or other
low volume methods, or applied by land or aerial irrigation systems.

[0120] Compositions for use as aqueous preparations (aqueous solutions or
dispersions) are generally supplied in the form of a concentrate
containing a high proportion of the active ingredient, the concentrate
being added to water before use. These concentrates, which may include
DCs, SCs, ECs, EWs, MEs, SGs, SPs, WPs, WGs and CSs, are often required
to withstand storage for prolonged periods and, after such storage, to be
capable of addition to water to form aqueous preparations which remain
homogeneous for a sufficient time to enable them to be applied by
conventional spray equipment. Such aqueous preparations may contain
varying amounts of a compound of formula (I) (for example 0.0001 to 10%,
by weight) depending upon the purpose for which they are to be used.

[0121] A compound of formula (I) may be used in mixtures with fertilizers
(for example nitrogen-, potassium- or phosphorus-containing fertilizers).
Suitable formulation types include granules of fertilizer. The mixtures
preferably contain up to 25% by weight of the compound of formula (I).

[0122] The invention therefore also provides a fertilizer composition
comprising a fertilizer and a compound of formula (I).

[0123] The compositions of this invention may contain other compounds
having biological activity, for example micronutrients or compounds
having fungicidal activity or which possess plant growth regulating,
herbicidal, insecticidal, nematicidal or acaricidal activity.

[0124] The compound of formula (I) may be the sole active ingredient of
the composition or it may be admixed with one or more additional active
ingredients such as a pesticide, e.g. a insecticide, fungicide or
herbicide, or a synergist or plant growth regulator where appropriate. An
additional active ingredient may provide a composition having a broader
spectrum of activity or increased persistence at a locus; synergize the
activity or complement the activity (for example by increasing the speed
of effect or overcoming repellency) of the compound of formula (I); or
help to overcome or prevent the development of resistance to individual
components. The particular additional active ingredient will depend upon
the intended utility of the composition. Examples of suitable pesticides
include the following:

[0127] y) 4-[(6-Chloro-pyridin-3-ylmethyl)-(2,2-difluoro-ethyl)-amino]-5H--
furan-2-one (DE 102006015467) In addition to the major chemical classes of
pesticide listed above, other pesticides having particular targets may be
employed in the composition, if appropriate for the intended utility of
the composition. For instance, selective insecticides for particular
crops, for example stemborer specific insecticides (such as cartap) or
hopper specific insecticides (such as buprofezin) for use in rice may be
employed. Alternatively insecticides or acaricides specific for
particular insect species/stages may also be included in the compositions
(for example acaricidal ovo-larvicides, such as clofentezine,
flubenzimine, hexythiazox or tetradifon; acaricidal motilicides, such as
dicofol or propargite; acaricides, such as bromopropylate or
chlorobenzilate; or growth regulators, such as hydramethylnon,
cyromazine, methoprene, chlorfluazuron or diflubenzuron).

[0129] The compounds of formula (I) may be mixed with soil, peat or other
rooting media for the protection of plants against seed-borne, soil-borne
or foliar fungal diseases.

[0130] Examples of suitable synergists for use in the compositions include
piperonyl butoxide, sesamex, safroxan and dodecyl imidazole.

[0131] Suitable herbicides and plant-growth regulators for inclusion in
the compositions will depend upon the intended target and the effect
required.

[0132] An example of a rice selective herbicide which may be included is
propanil. An example of a plant growth regulator for use in cotton is
PIX®.

[0133] Some mixtures may comprise active ingredients which have
significantly different physical, chemical or biological properties such
that they do not easily lend themselves to the same conventional
formulation type. In these circumstances other formulation types may be
prepared. For example, where one active ingredient is a water insoluble
solid and the other a water insoluble liquid, it may nevertheless be
possible to disperse each active ingredient in the same continuous
aqueous phase by dispersing the solid active ingredient as a suspension
(using a preparation analogous to that of an SC) but dispersing the
liquid active ingredient as an emulsion (using a preparation analogous to
that of an EW). The resultant composition is a suspoemulsion (SE)
formulation.

[0134] The compounds of the invention are also useful in the field of
animal health, e.g. they may be used against parasitic invertebrate
pests, more preferably against parasitic invertebrate pests in or on an
animal. Examples of pests include nematodes, trematodes, cestodes, flies,
mites, tricks, lice, fleas, true bugs and maggots. The animal may be a
non-human animal, e.g. an animal associated with agriculture, e.g. a cow,
a pig, a sheep, a goat, a horse, or a donkey, or a companion animal, e.g.
a dog or a cat.

[0135] In a further aspect the invention provides a compound of the
invention for use in a method of therapeutic treatment.

[0136] In a further aspect the invention relates to a method of
controlling parasitic invertebrate pests in or on an animal comprising
administering a pesticidally effective amount of a compound of the
invention. The administration may be for example oral administration,
parenteral administration or external administration, e.g. to the surface
of the animal body. In a further aspect the invention relates to a
compound of the invention for controlling parasitic invertebrate pests in
or on an animal. In a further aspect the invention relates to use of a
compound of the invention in the manufacture of a medicament for
controlling parasitic invertebrate pests in or on an animal

[0137] In a further aspect, the invention relates to a method of
controlling parasitic invertebrate pests comprising administering a
pesticidally effective amount of a compound of the invention to the
environment in which an animal resides.

[0138] In a further aspect the invention relates to a method of protecting
an animal from a parasitic invertebrate pest comprising administering to
the animal a pesticidally effective amount of a compound of the
invention. In a further aspect the invention relates to a compound of the
invention for use in protecting an animal from a parasitic invertebrate
pest. In a further aspect the invention relates to use of a compound of
the invention in the manufacture of a medicament for protecting an animal
from a parasitic invertebrate pest.

[0139] In a further aspect the invention provides a method of treating an
animal suffering from a parasitic invertebrate pest comprising
administering to the animal a pesticidally effective amount of a compound
of the invention. In a further aspect the invention relates to a compound
of the invention for use in treating an animal suffering from a parasitic
invertebrate pest. In a further aspect the invention relates to use of a
compound of the invention in the manufacture of a medicament for treating
an animal suffering from a parasitic invertebrate pest.

[0140] In a further aspect, the invention provides a pharmaceutical
composition comprising a compound of the invention and a pharmaceutically
suitable excipient.

[0141] The compounds of the invention may be used alone or in combination
with one or more other biologically active ingredients.

[0142] In one aspect the invention provides a combination product
comprising a pesticidally effective amount of a component A and a
pesticidally effective amount of component B wherein component A is a
compound of the invention and component B is a compound as described
below.

[0143] The compounds of the invention may be used in combination with
anthelmintic agents. Such anthelmintic agents include, compounds selected
from the macrocyclic lactone class of compounds such as ivermectin,
avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin,
moxidectin, nemadectin and milbemycin derivatives as described in
EP-357460, EP-444964 and EP-594291. Additional anthelmintic agents
include semisynthetic and biosynthetic avermectin/milbemycin derivatives
such as those described in U.S. Pat. No. 5,015,630, WO-9415944 and
WO-9522552. Additional anthelmintic agents include the benzimidazoles
such as albendazole, cambendazole, fenbendazole, flubendazole,
mebendazole, oxfendazole, oxibendazole, parbendazole, and other members
of the class. Additional anthelmintic agents include imidazothiazoles and
tetrahydropyrimidines such as tetramisole, levamisole, pyrantel pamoate,
oxantel or morantel. Additional anthelmintic agents include flukicides,
such as triclabendazole and clorsulon and the cestocides, such as
praziquantel and epsiprantel.

[0144] The compounds of the invention may be used in combination with
derivatives and analogues of the paraherquamide/marcfortine class of
anthelmintic agents, as well as the antiparasitic oxazolines such as
those disclosed in U.S. Pat. No. 5,478,855, U.S. Pat. No. 4,639,771 and
DE-19520936.

[0145] The compounds of the invention may be used in combination with
derivatives and analogues of the general class of dioxomorpholine
antiparasitic agents as described in WO-9615121 and also with
anthelmintic active cyclic depsipeptides such as those described in
WO-9611945, WO-9319053, WO-9325543, EP-626375, EP-382173, WO-9419334,
EP-382173, and EP-503538.

[0146] The compounds of the invention may be used in combination with
other ectoparasiticides; for example, fipronil; pyrethroids;
organophosphates; insect growth regulators such as lufenuron; ecdysone
agonists such as tebufenozide and the like; neonicotinoids such as
imidacloprid and the like.

[0147] The compounds of the invention may be used in combination with
terpene alkaloids, for example those described in International Patent
Application Publication Numbers WO95/19363 or WO04/72086, particularly
the compounds disclosed therein.

[0148] Other examples of such biologically active compounds that the
compounds of the invention may be used in combination with include but
are not restricted to the following:

[0159] Of particular note is a combination where the additional active
ingredient has a different site of action from the compound of formula I.
In certain instances, a combination with at least one other parasitic
invertebrate pest control active ingredient having a similar spectrum of
control but a different site of action will be particularly advantageous
for resistance management. Thus, a combination product of the invention
may comprise a pesticidally effective amount of a compound of formula I
and pesticidally effective amount of at least one additional parasitic
invertebrate pest control active ingredient having a similar spectrum of
control but a different site of action.

[0160] One skilled in the art recognizes that because in the environment
and under physiological conditions salts of chemical compounds are in
equilibrium with their corresponding non salt forms, salts share the
biological utility of the non salt forms. Thus a wide variety of salts of
compounds of the invention (and active ingredients used in combination
with the active ingredients of the invention) may be useful for control
of invertebrate pests and animal parasites. Salts include acid-addition
salts with inorganic or organic acids such as hydrobromic, hydrochloric,
nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic,
malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or
valeric acids. The compounds of the invention also include N-oxides.
Accordingly, the invention comprises combinations of compounds of the
invention including N-oxides and salts thereof and an additional active
ingredient including N-oxides and salts thereof.

[0161] The compositions for use in animal health may also contain
formulation auxiliaries and additives, known to those skilled in the art
as formulation aids (some of which may be considered to also function as
solid diluents, liquid diluents or surfactants). Such formulation
auxiliaries and additives may control: pH (buffers), foaming during
processing (antifoams such polyorganosiloxanes), sedimentation of active
ingredients (suspending agents), viscosity (thixotropic thickeners),
in-container microbial growth (antimicrobials), product freezing
(antifreezes), color (dyes/pigment dispersions), wash-off (film formers
or stickers), evaporation (evaporation retardants), and other formulation
attributes. Film formers include, for example, polyvinyl acetates,
polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate
copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes.
Examples of formulation auxiliaries and additives include those listed in
McCutcheon's Volume 2: Functional Materials, annual International and
North American editions published by McCutcheon's Division, The
Manufacturing Confectioner Publishing Co.; and PCT Publication WO
03/024222.

[0162] The compounds of the invention can be applied without other
adjuvants, but most often application will be of a formulation comprising
one or more active ingredients with suitable carriers, diluents, and
surfactants and possibly in combination with a food depending on the
contemplated end use. One method of application involves spraying a water
dispersion or refined oil solution of the combination products.
Compositions with spray oils, spray oil concentrations, spreader
stickers, adjuvants, other solvents, and synergists such as piperonyl
butoxide often enhance compound efficacy. Such sprays can be applied from
spray containers such as a can, a bottle or other container, either by
means of a pump or by releasing it from a pressurized container, e.g., a
pressurized aerosol spray can. Such spray compositions can take various
forms, for example, sprays, mists, foams, fumes or fog. Such spray
compositions thus can further comprise propellants, foaming agents, etc.
as the case may be. Of note is a spray composition comprising a
pesticidally effective amount of a compound of the invention and a
carrier. One embodiment of such a spray composition comprises a
pesticidally effective amount of a compound of the invention and a
propellant. Representative propellants include, but are not limited to,
methane, ethane, propane, butane, isobutane, butene, pentane, isopentane,
neopentane, pentene, hydrofluorocarbons, chlorofluorocarbons, dimethyl
ether, and mixtures of the foregoing. Of note is a spray composition (and
a method utilizing such a spray composition dispensed from a spray
container) used to control at least one parasitic invertebrate pest
selected from the group consisting of mosquitoes, black flies, stable
flies, deer flies, horse flies, wasps, yellow jackets, hornets, ticks,
spiders, ants, gnats, and the like, including individually or in
combinations.

[0163] The controlling of animal parasites includes controlling external
parasites that are parasitic to the surface of the body of the host
animal (e.g., shoulders, armpits, abdomen, inner part of the thighs) and
internal parasites that are parasitic to the inside of the body of the
host animal (e.g., stomach, intestine, lung, veins, under the skin,
lymphatic tissue). External parasitic or disease transmitting pests
include, for example, chiggers, ticks, lice, mosquitoes, flies, mites and
fleas. Internal parasites include heartworms, hookworms and helminths.
The compounds of the invention may be particularly suitable for combating
external parasitic pests. The compounds of the invention may be suitable
for systemic and/or non-systemic control of infestation or infection by
parasites on animals.

[0164] The compounds of the invention may be suitable for combating
parasitic invertebrate pests that infest animal subjects including those
in the wild, livestock and agricultural working animals. Livestock is the
term used to refer (singularly or plurally) to a domesticated animal
intentionally reared in an agricultural setting to make produce such as
food or fiber, or for its labor; examples of livestock include cattle,
sheep, goats, horses, pigs, donkeys, camels, buffalo, rabbits, hens,
turkeys, ducks and geese (e.g., raised for meat, milk, butter, eggs, fur,
leather, feathers and/or wool). By combating parasites, fatalities and
performance reduction (in terms of meat, milk, wool, skins, eggs, etc.)
are reduced, so that applying the compounds of the invention allows more
economic and simple husbandry of animals.

[0165] The compounds of the invention may be suitable for combating
parasitic invertebrate pests that infest companion animals and pets
(e.g., dogs, cats, pet birds and aquarium fish), research and
experimental animals (e.g., hamsters, guinea pigs, rats and mice), as
well as animals raised for/in zoos, wild habitats and/or circuses.

[0167] Birds treated or protected by the compounds of the invention can be
associated with either commercial or noncommercial aviculture. These
include Anatidae, such as swans, geese, and ducks, Columbidae, such as
doves and domestic pigeons, Phasianidae, such as partridge, grouse and
turkeys, Thesienidae, such as domestic chickens, and Psittacines, such as
parakeets, macaws and parrots raised for the pet or collector market,
among others.

[0168] For purposes of the present invention, the term "fish" is
understood to include without limitation, the Teleosti grouping of fish,
i.e., teleosts. Both the Salmoniformes order (which includes the
Salmonidae family) and the Perciformes order (which includes the
Centrarchidae family) are contained within the Teleosti grouping.
Examples of potential fish recipients include the Salmonidae, Serranidae,
Sparidae, Cichlidae, and Centrarchidae, among others.

[0169] Other animals are also contemplated to benefit from the inventive
methods, including marsupials (such as kangaroos), reptiles (such as
farmed turtles), and other economically important domestic animals for
which the inventive methods are safe and effective in treating or
preventing parasite infection or infestation.

[0170] Examples of parasitic invertebrate pests controlled by
administering a pesticidally effective amount of the compounds of the
invention to an animal to be protected include ectoparasites (arthropods,
acarines, etc.) and endoparasites (helminths, e.g., nematodes,
trematodes, cestodes, acanthocephalans, etc.).

[0171] The disease or group of diseases described generally as
helminthiasis is due to infection of an animal host with parasitic worms
known as helminths. The term `helminths` is meant to include nematodes,
trematodes, cestodes and acanthocephalans. Helminthiasis is a prevalent
and serious economic problem with domesticated animals such as swine,
sheep, horses, cattle, goats, dogs, cats and poultry.

[0173] Of the above, the most common genera of nematodes infecting the
animals referred to above are Haemonchus, Trichostrongylus, Ostertagia,
Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia,
Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis,
Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and
Parascaris. Certain of these, such as Nematodirus, Cooperia and
Oesophagostomum attack primarily the intestinal tract while others, such
as Haemonchus and Ostertagia, are more prevalent in the stomach while
others such as Dictyocaulus are found in the lungs. Still other parasites
may be located in other tissues such as the heart and blood vessels,
subcutaneous and lymphatic tissue and the like.

[0174] Trematodes that are contemplated to be treated by the invention and
by the inventive methods include, without limitation, the following
genera: Alaria, Fasciola, Nanophyetus, Opisthorchis, Paragonimus and
Schistosoma.

[0175] Cestodes that are contemplated to be treated by the invention and
by the inventive methods include, without limitation, the following
genera: Diphyllobothrium, Diplydium, Spirometra and Taenia.

[0176] The most common genera of parasites of the gastrointestinal tract
of humans are Ancylostoma, Necator, Ascaris, Strongy hides, Trichinella,
Capillaria, Trichuris and Enterobius. Other medically important genera of
parasites which are found in the blood or other tissues and organs
outside the gastrointestinal tract are the filarial worms such as
Wuchereria, Brugia, Onchocerca and Loa, as well as Dracunculus and extra
intestinal stages of the intestinal worms Strongyloides and Trichinella.

[0177] Numerous other helminth genera and species are known to the art,
and are also contemplated to be treated by the compounds of the
invention. These are enumerated in great detail in Textbook of Veterinary
Clinical Parasitology, Volume 1, Helminths, E. J. L. Soulsby, F. A. Davis
Co., Philadelphia, Pa.; Helminths, Arthropods and Protozoa, (6th
Edition of Monnig's Veterinary Helminthology and Entomology), E. J. L.
Soulsby, Williams and Wilkins Co., Baltimore, Md.

[0178] The compounds of the invention may be effective against a number of
animal ectoparasites (e.g., arthropod ectoparasites of mammals and
birds).

[0180] Adult flies include, e.g., the horn fly or Haematobia irritans, the
horse fly or Tabanus spp., the stable fly or Stomoxys calcitrans, the
black fly or Simulium spp., the deer fly or Chrysops spp., the louse fly
or Melophagus ovinus, and the tsetse fly or Glossina spp. Parasitic fly
maggots include, e.g., the bot fly (Oestrus ovis and Cuterebra spp.), the
blow fly or Phaenicia spp., the screwworm or Cochliomyia hominivorax, the
cattle grub or Hypoderma spp., the fleeceworm and the Gastrophilus of
horses. Mosquitoes include, for example, Culex spp., Anopheles spp. and
Aedes spp.

[0181] Mites include Mesostigmalphatalpha spp. e.g., mesostigmatids such
as the chicken mite, Dermalphanyssus galphallinalphae; itch or scab mites
such as Sarcoptidae spp. for example, Salpharcoptes scalphabiei; mange
mites such as Psoroptidae spp. including Chorioptes bovis and Psoroptes
ovis; chiggers e.g., Trombiculidae spp. for example the North American
chigger, Trombiculalpha alphalfreddugesi.

[0186] Generally, flies, fleas, lice, mosquitoes, gnats, mites, ticks and
helminths cause tremendous losses to the livestock and companion animal
sectors. Arthropod parasites also are a nuisance to humans and can vector
disease-causing organisms in humans and animals.

[0187] Numerous other parasitic invertebrate pests are known to the art,
and are also contemplated to be treated by the compounds of the
invention. These are enumerated in great detail in Medical and Veterinary
Entomology, D. S. Kettle, John Wiley AND Sons, New York and Toronto;
Control of Arthropod Pests of Livestock: A Review of Technology, R. O.
Drummand, J. E. George, and S. E. Kunz, CRC Press, Boca Raton, FIa.

[0189] Treatments of the invention are by conventional means such as by
enteral administration in the form of, for example, tablets, capsules,
drinks, drenching preparations, granulates, pastes, boli, feed-through
procedures, or suppositories; or by parenteral administration, such as,
for example, by injection (including intramuscular, subcutaneous,
intravenous, intraperitoneal) or implants; or by nasal administration.

[0190] When compounds of the invention are applied in combination with an
additional biologically active ingredient, they may be administered
separately e.g. as separate compositions. In this case, the biologically
active ingredients may be administered simultaneously or sequentially.
Alternatively, the biologically active ingredients may be components of
one composition.

[0191] The compounds of the invention may be administered in a controlled
release form, for example in subcutaneous or orally adminstered slow
release formulations.

[0192] Typically a parasiticidal composition according to the present
invention comprises a compound of the invention, optionally in
combination with an additional biologically active ingredient, or
N-oxides or salts thereof, with one or more pharmaceutically or
veterinarily acceptable carriers comprising excipients and auxiliaries
selected with regard to the intended route of administration (e.g., oral
or parenteral administration such as injection) and in accordance with
standard practice. In addition, a suitable carrier is selected on the
basis of compatibility with the one or more active ingredients in the
composition, including such considerations as stability relative to pH
and moisture content. Therefore of note are compounds of the invention
for protecting an animal from an invertebrate parasitic pest comprising a
parasitically effective amount of a compound of the invention, optionally
in combination with an additional biologically active ingredient and at
least one carrier.

[0193] For parenteral administration including intravenous, intramuscular
and subcutaneous injection, the compounds of the invention can be
formulated in suspension, solution or emulsion in oily or aqueous
vehicles, and may contain adjuncts such as suspending, stabilizing and/or
dispersing agents.

[0194] The compounds of the invention may also be formulated for bolus
injection or continuous infusion. Pharmaceutical compositions for
injection include aqueous solutions of water-soluble forms of active
ingredients (e.g., a salt of an active compound), preferably in
physiologically compatible buffers containing other excipients or
auxiliaries as are known in the art of pharmaceutical formulation.
Additionally, suspensions of the active compounds may be prepared in a
lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such
as sesame oil, synthetic fatty acid esters such as ethyl oleate and
triglycerides, or materials such as liposomes.

[0195] Aqueous injection suspensions may contain substances that increase
the viscosity of the suspension, such as sodium carboxymethyl cellulose,
sorbitol, or dextran. Formulations for injection may be presented in unit
dosage form, e.g., in ampoules or in multi-dose containers.
Alternatively, the active ingredient may be in powder form for
constitution with a suitable vehicle, e.g., sterile, pyrogen-free water,
before use.

[0196] In addition to the formulations described supra, the compounds of
the invention may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation (for example,
subcutaneously or intramuscularly) or by intramuscular or subcutaneous
injection.

[0197] The compounds of the invention may be formulated for this route of
administration with suitable polymeric or hydrophobic materials (for
instance, in an emulsion with a pharmacologically acceptable oil), with
ion exchange resins, or as a sparingly soluble derivative such as,
without limitation, a sparingly soluble salt.

[0198] For administration by inhalation, the compounds of the invention
can be delivered in the form of an aerosol spray using a pressurized pack
or a nebulizer and a suitable propellant, e.g., without limitation,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized
aerosol, the dosage unit may be controlled by providing a valve to
deliver a metered amount.

[0199] Capsules and cartridges of, for example, gelatin for use in an
inhaler or insufflator may be formulated containing a powder mix of the
compound and a suitable powder base such as lactose or starch.

[0200] The compounds of the invention may have favourable pharmacokinetic
and pharmacodynamic properties providing systemic availability from oral
administration and ingestion. Therefore after ingestion by the animal to
be protected, parasiticidally effective concentrations of a compound of
the invention in the bloodstream may protect the treated animal from
blood-sucking pests such as fleas, ticks and lice. Therefore of note is a
composition for protecting an animal from an invertebrate parasite pest
in a form for oral administration (i.e. comprising, in addition to a
parasiticidally effective amount of a compound of the invention, one or
more carriers selected from binders and fillers suitable for oral
administration and feed concentrate carriers).

[0201] For oral administration in the form of solutions (the most readily
available form for absorption), emulsions, suspensions, pastes, gels,
capsules, tablets, boluses, powders, granules, rumen-retention and
feed/water/lick blocks, the compounds of the invention can be formulated
with binders/fillers known in the art to be suitable for oral
administration compositions, such as sugars and sugar derivatives (e.g.,
lactose, sucrose, mannitol, sorbitol), starch (e.g., maize starch, wheat
starch, rice starch, potato starch), cellulose and derivatives (e.g.,
methylcellulose, carboxymethylcellulose, ethylhydroxycellulose), protein
derivatives (e.g., zein, gelatin), and synthetic polymers (e.g.,
polyvinyl alcohol, polyvinylpyrrolidone). If desired, lubricants (e.g.,
magnesium stearate), disintegrating agents (e.g., cross-linked
polyvinylpyrrolidinone, agar, alginic acid) and dyes or pigments can be
added. Pastes and gels often also contain adhesives (e.g., acacia,
alginic acid, bentonite, cellulose, xanthan gum, colloidal magnesium
aluminum silicate) to aid in keeping the composition in contact with the
oral cavity and not being easily ejected.

[0202] In one embodiment a composition of the present invention is
formulated into a chewable and/or edible product (e.g., a chewable treat
or edible tablet). Such a product would ideally have a taste, texture
and/or aroma favored by the animal to be protected so as to facilitate
oral administration of the compounds of the invention.

[0203] If the parasiticidal compositions are in the form of feed
concentrates, the carrier is typically selected from high-performance
feed, feed cereals or protein concentrates. Such feed
concentrate-containing compositions can, in addition to the parasiticidal
active ingredients, comprise additives promoting animal health or growth,
improving quality of meat from animals for slaughter or otherwise useful
to animal husbandry. These additives can include, for example, vitamins,
antibiotics, chemotherapeutics, bacteriostats, fungistats, coccidiostats
and hormones.

[0204] The compound of the invention may also be formulated in rectal
compositions such as suppositories or retention enemas, using, e.g.,
conventional suppository bases such as cocoa butter or other glycerides.

[0205] The formulations for the method of this invention may include an
antioxidant, such asBHT (butylated hydroxytoluene). The antioxidant is
generally present in amounts of at 0.1-5 percent (wt/vol). Some of the
formulations require a solubilizer, such as oleic acid, to dissolve the
active agent, particularly if spinosad is included. Common spreading
agents used in these pour-on formulations include isopropyl myristate,
isopropyl palmitate, caprylic/capric acid esters of saturated
C12-C18 fatty alcohols, oleic acid, oleyl ester, ethyl oleate,
triglycerides, silicone oils and dipropylene glycol methyl ether. The
pour-on formulations for the method of this invention are prepared
according to known techniques. Where the pour-on is a solution, the
parasiticide/insecticide is mixed with the carrier or vehicle, using heat
and stirring if required. Auxiliary or additional ingredients can be
added to the mixture of active agent and carrier, or they can be mixed
with the active agent prior to the addition of the carrier. Pour-on
formulations in the form of emulsions or suspensions are similarly
prepared using known techniques.

[0206] Other delivery systems for relatively hydrophobic pharmaceutical
compounds may be employed. Liposomes and emulsions are well-known
examples of delivery vehicles or carriers for hydrophobic drugs. In
addition, organic solvents such as dimethylsulfoxide may be used, if
needed.

[0207] The rate of application required for effective parasitic
invertebrate pest control (e.g. "pesticidally effective amount") will
depend on such factors as the species of parasitic invertebrate pest to
be controlled, the pest's life cycle, life stage, its size, location,
time of year, host crop or animal, feeding behavior, mating behavior,
ambient moisture, temperature, and the like. One skilled in the art can
easily determine the pesticidally effective amount necessary for the
desired level of parasitic invertebrate pest control.

[0208] In general for veterinary use, the compounds of the invention are
administered in a pesticidally effective amount to an animal,
particularly a homeothermic animal, to be protected from parasitic
invertebrate pests.

[0209] A pesticidally effective amount is the amount of active ingredient
needed to achieve an observable effect diminishing the occurrence or
activity of the target parasitic invertebrate pest. One skilled in the
art will appreciate that the pesticidally effective dose can vary for the
various compounds and compositions useful for the method of the present
invention, the desired pesticidal effect and duration, the target
parasitic invertebrate pest species, the animal to be protected, the mode
of application and the like, and the amount needed to achieve a
particular result can be determined through simple experimentation.

[0210] For oral or parenteral administration to animals, a dose of the
compositions of the present invention administered at suitable intervals
typically ranges from about 0.01 mg/kg to about 100 mg/kg, and preferably
from about 0.01 mg/kg to about 30 mg/kg of animal body weight.

[0211] Suitable intervals for the administration of the compositions of
the present invention to animals range from about daily to about yearly.
Of note are administration intervals ranging from about weekly to about
once every 6 months. Of particular note are monthly administration
intervals (i.e. administering the compounds to the animal once every
month).

[0212] The following Examples illustrate, but do not limit, the invention.

[0230] Oxalyl chloride (0.122 ml) was added to a solution of
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-benzoic acid (0.5 g) (prepared according to WO 2009/080250) in
dichloromethane (3 ml). After addition of two drops of
N,N-dimethylformamide ("DMF") the reaction mixture was stirred at ambient
temperature for 18 hours. The reaction mixture was concentrated to give
the acid chloride as a yellow solid, which was used in the next step
without further purification.

[0234] ((R)-2-methyl-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl
ester of Step A (108 mg) was dissolved in dichloromethane (5 ml) and
treated with trifluoroacetic acid (0.2 ml). The reaction mixture was
stirred at room temperature for 1 hour and the solvent removed in vacuo
to afford (R)-4-Amino-2-methyl-isoxazolidin-3-one (trifluoroacetic acid
salt), which was used directly in the next step.

[0242] When this reaction was carried out to obtain
4-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl-
]-2-methyl-N--((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (compound
C1), it was possible to separate the two diastereoisomers by
precipitation after the work up. The crude mixture was stirred with
diethyl ether and a solid precipitated out of the solution. The solid
(enriched in 1 diastereomer) was analysed by chiral HPLC (method K): 9.72
min (93.8%), 16.6 min (06.17%). The filtrate (enriched in the other
diastereomer) was also analysed by chiral HPLC (method K): 9.99 min
(11.53%), 16.6 min (85.16%).

[0243] Similarly when this reaction was carried out to obtain
4-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-
l-3-yl]-2-methyl-N--((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide
(compound C3), it was possible to separate the two diastereoisomers by
precipitation after the work up. The crude mixture was stirred with
diethyl ether and a solid precipitated out of the solution. The solid
(enriched in 1 diastereomer) was analysed by chiral HPLC (method K): 8.88
min (88.87%), 15.98 min (05.95%). The filtrate (enriched in the other
diastereomer) was also analysed by chiral HPLC (method K): 8.61 min
(24.10%), 12.25 min (74.49%).

[0246] The BOC protecting group was removed as described in Example 3,
Step B to afford (R)-4-amino-2-(2-hydroxyethyl)-isoxazolidin-3-one
(trifluoroacetic acid salt), which was used directly in the next step.

[0250] Using the product obtained in Step A (43 mg), the BOC protecting
group was removed as described in Example 3, Step B to afford the title
product, which was used diretly in the next step. LCMS (Method A) 0.17
min, M-H 175.

[0251] Amide coupling was performed as described in Example 3, Step C to
afford the title compound as a yellow resin (10 mg); LCMS (Method A) 2.13
min, M-H 573/574.

[0252] The following compounds were prepared following a similar method to
that described in Example 6:
4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-N--((R)-2-(cyclobutyl)-3-oxo-isoxazolidin-4-yl)-benzamide
(compound B11);
4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-N--((R)-2-(oxetan-3-yl)-3-oxo-isoxazolidin-4-yl)-benzamide
(compound B12)

EXAMPLE 7

General Method for Preparing the Compounds of the Invention in Parallel

##STR00033##

[0254] To a solution of
4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-N--((R)-3-oxo-isoxazolidin-4-yl)-benzamide (30 μmol) in
N,N-dimethylformamide ("DMF") (0.5 ml) was added a solution of an
alkylhalogenide of formula R-X (32 μmmol) in N,N-dimethylformamide
("DMF") (0.3 ml) followed by addition of potassium carbonate (80
μmol). The reaction mixture was stirred at ambient temperature for 16
hours. Then the reaction mixture was separated by HPLC. This method was
used to prepare a number of compounds (Compound Nos. B13 to B29 of Table
B) in parallel.

[0257] Oxalyl chloride (0.027 ml) was added to a solution of
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-benzoic acid (100 mg) (prepared according to WO 2009/080250) in
dichloromethane (1.2 ml). After addition of two drops of
N,N-dimethylformamide ("DMF") the reaction mixture was stirred at ambient
temperature for 18 hours. The reaction mixture was concentrated to give
the acid chloride as a yellow solid, which was used in the next step
without further purification.

[0261] Benzenesulfonyl chloride (0.41 ml, 1.1 equiv) was added to a
solution of N-(3-Benzyloxy-2-hydroxy-propyl)-N-ethyl-methanesulfonamide
(836 mg, 2.91 mmol) in pyridine (5.8 ml). The reaction mixture was then
heated to 50° C. for 24 hours. Ethyl acetate was added and a
precipitate (pyridinium hydrochloride salt) formed. It was filtered and
the residue was diluted in ethyl acetate. The organic phase was then
washed with 1M aqueous HCl, water, CuSO4 aqueous solution and
NaHCO3 saturated aqueous solution. The organic phase was then dried
(Na2SO4) and evaporated.

[0263] A mixture of 4-Benzyloxymethyl-2-ethyl-isothiazolidine 1,1-dioxide
(254 mg) and Pd/C (108 mg, 0.1 equiv) in methanol was purged with H2
and left to stir under an H2 atmosphere for 24 h. As LCMS indicated
completion, the reaction mixture was filtered through a pad of silica
(rinsing with MeOH). The filtrate was evaporated and 162 mg of the
expected acohol were obtained. It was pure enough to be used as such in
the next step. LCMS (Method E) 0.25 min, M+H 170. 1H-NMR
(CDCl3, 400 MHz): 3.8-3.70 (m, 2H), 3.39-3.25 (m, 2H), 3.20-3.01 (m,
4H), 2.94-2.78 (m, 1H), 1.24 (t, 3H).

[0265] To a solution of
2-(2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-ylmethyl)-isoindole-1,3--
dione (261 mg, 0.85 mmol) in EtOH (4 ml) was added hydrazine monohydrate
(0.165 ml, 4 equiv). The reaction mixture was then refluxed overnight and
a white gum formed. The reaction mixture was filtered (rinsing several
times with EtOH) and the filtrate was evaporated to afford 81 mg of the
expected amine contaminated by 10% of 2,3-Dihydro-phthalazine-1,4-dione.
It was used as such in the next step.

[0267] Oxalyl chloride (0.027 ml) was added to a solution of
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-benzoic acid (100 mg) (prepared according to WO 2009/080250) in
dichloromethane (1.2 ml). After addition of two drops of
N,N-dimethylformamide ("DMF") the reaction mixture was stirred at ambient
temperature for 18 hours. The reaction mixture was concentrated to give
the acid chloride as a yellow solid, which was used in the next step
without further purification.

[0272] Oxalyl chloride (0.037 ml) was added to a solution of
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-benzoic acid (135 mg) (prepared according to WO 2009/080250) in
dichloromethane (1.6 ml). After addition of two drops of
N,N-dimethylformamide ("DMF") the reaction mixture was stirred at ambient
temperature for 18 hours. The reaction mixture was concentrated to give
the acid chloride as a yellow solid, which was used in the next step
without further purification.

[0274] 2-[4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carbonyl]-benzo-
ic acid methyl ester (2.67 g, 6.14 mmol) was suspended in 20 ml 2M aqueous
HCl and the mixture was refluxed for 48 hours. It was then filtered and
the solids were washed with water. The filtrate was then evaporated and
dried under vacuum. The residue was triturated in i-PrOH. The solid was
filtered and the filtrate evaporated. This filtrate (177 mg) was used as
such without further purification. LCMS (Method E) 0.87 and 0.95 min, M+H
274.

[0277] Oxalyl chloride (0.20 ml) was added to a solution of
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-benzoic acid (749 mg) (prepared according to WO 2009/080250) in
dichloromethane (9 ml). After addition of two drops of
N,N-dimethylformamide ("DMF") the reaction mixture was stirred at ambient
temperature for 18 hours. The reaction mixture was concentrated to give
the acid chloride as a yellow solid, which was used in the next step
without further purification.

[0278] To a solution of the acid chloride in dichloromethane (18 ml) were
added triethylamine (0.30 ml) followed by
4-Amino-isoxazolidine-2-carboxylic acid tert-butyl ester (336 mg). The
reaction mixture was then stirred at room temperature for 24 hours. The
reaction was quenched by adding water and the mixture extracted with
ethyl acetate. The combined organic layers were washed with brine, dried
(Na2SO4) and evaporated. Flash column chromatography eluting
with cyclohexane/EtOAc (1/1) afforded 197 mg the expected amine as a
mixture of diastereomers.

[0284] A solution of
4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(2,3-dih-
ydroxy-propyl)-2-methylbenzamide (100 mg, 0.2 mmol) in dichloromethane (10
ml) was cooled to 0° C., treated with Pyridine (0.08 ml, 1.0 mmol)
and thionyl chloride (0.03, 0.4 mmol), and stirred for 6 hours. The
mixture was diluted with dichloromethane (50 ml), neutralized with 2N
hydrochloric acid and washed with water (50 ml). The organic layer was
separated, dried over sodium sulfate and concentrated to give the title
compound (65 mg) as a mixture of diastereoisomers. Purification by
preparative HPLC gave the diastereoisomer 1 (28 mg) and the
diastereoisomer 2 (18 mg);

[0287] Following the procedure described in Tetrahedron 55, 1999,
4685-4698, N--BOC-allylamine (2 g) was dissolved in toluene (130 ml) and
ethanol (45 ml) then benzylhydroxylamine hydrochloride (3.05 g),
paraformaldehyde (3.16 g) and triethylamine (1.93 g) were added. The
reaction mixture was allowed to stir at room temperature for 24 hours,
then the solvent was evaporated in vacuo. The resulting residue was
diluted in ethyl acetate and the hydrochloride salt of triethylamine was
filtered off. The filtrate was concentrated in vacuo and the residue
purified by column chromatography (ethyl acetate/cyclohexane 1:1) to
afford the title compound as a colorless oil (4.37 g). LCMS (Method F)
1.53 min, M+H 293.

Step B: C-(2-Benzyl-isoxazolidin-5-yl)-methylamine

##STR00053##

[0288] A solution of (2-benzyl-isoxazolidin-5-ylmethyl)-carbamic acid
tert-butyl ester (Step A, 0.5 g) in dichloromethane (10 ml) was treated
with trifluoroacetic acid (1.95 g). The solution was stirred at room
temperature for 4 hours then concentrated in vacuo to afford the crude
title product, which was used directly for the next step. LCMS (Method F)
0.20 min, M+H 194.

[0290] The following compound was prepared following a similar method to
that described in Example 12:
N-(2-methyl-isoxazolidin-5-ylmethyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluo-
romethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide (compound F2).

[0292] Following the procedure described in Tetrahedron 46, 1990,
1975-1986, N--BOC-allylamine (1.8 g) was dissolved in ethyl acetate and
treated with sodium hydrogenocarbonate (4.38 g) and dibromoformaldoxime
(2.55 g). The reaction mixture was stirred at room temperature for 4
hours, then poured into water, extracted with ethyl acetate, the organic
layer was dried over sodium sulfate and the solvent removed in vacuo. The
title crude product was thus obtained as a colorless oil (3.16 g). LCMS
(Method F) 1.48 min, M+H 179/181 (M-BOC).

[0295] A solution of the product obtained in Step C in dichloromethane (2
ml) was treated with trifluoroacetic acid (0.15 g). The solution was
stirred at room temperature for 4 hours then concentrated in vacuo to
afford the crude title product, which was used directly for the next
step. LCMS (Method F) 0.18 min, M+H 145.

[0296] 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-
-yl]-2-methyl-benzoic acid (0.3 g) (prepared according to WO 2009/080250)
was coupled with the amine obtained in Step D (0.12 g) as described in
Example 12, Step C to afford the title product as a beige solid (62 mg,
mixture of diasteroisomers). LCMS (Method F) 2.02 min, M+H 542/544.

[0297] The following compound was prepared following a similar method to
that described in Example 13:
4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-N-[3-oxo-2-(1,1,1-trifluoroethyl)-isoxazolidin-5-ylmethyl]-benzami-
de (compound F4).

[0301] To a solution at 0° C. of the product obtained in Step B
(500 mg) in methanol (15 ml) were added di-tert-butyldicarbonate (807 mg)
and nickel (II) chloride hexahydrate (90 mg). Sodium borohydride (490 mg)
was added portionwise. The reaction mixture was allowed to stir at room
temperature for 24 hours. Diethylenetriamine (190 mg) was added, the
reaction mixture was stirred for 30 min at room temperature then the
solvent was removed in vacuo. The purple solid residue was diluted in
ethyl acetate then washed with aqueous saturated hydrogen bicarbonate.
The aqueous layer was extracted with ethyl acetate, the combined organic
layers were dried over sodium sulfate and concentrated in vacuo.
Purification using the Combi Flash200 afforded the title product as an
impure brown oil (80 mg), which was used directly in the next step.

[0302] The compound obtained in Step C (94 mg) was deprotected and coupled
with 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3--
yl]-2-methyl-benzoic acid (0.125 g) (prepared according to WO 2009/080250)
as described in Example 4, Steps B and C to afford the title compound as
a brown solid (65 mg). LCMS (Method F) 2.02 min, M-H 654/655.

[0303] The following compounds were prepared following a similar method to
that described in Example 14:
4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-
-[2-(2,2,2-trifluoroethyl)-1,1-dioxo-1lambda*6*-isothiazolidin-5-ylmethyl]-
-2-methyl-benzamide (Compound F7).

[0312] The BOC protecting group was removed as described in Example 4,
Step B to afford (R)-4-amino-2-(2,2-difluoroethyl)-isoxazolidin-3-one
(trifluoroacetic acid salt), which was used directly in the next step.

[0314] The following compound was prepared following a similar method to
that described in Example 16:
4-[5-(3,5-Dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-y-
l]-2-methyl-N--((R)-2-(2,2-difluoroethyl)-3-oxo-isoxazolidin-4-yl)-benzami-
de (compound G5).

[0316] To a solution of 2,5-dibromo-4-methylpyridine (2 g) in acetonitrile
(40 ml) at room temperature under argon were added sodium iodide (4.8 g)
then acetyl chloride (0.94 g). After 3 hours stirring at room temperature
the white solid formed was filtered off and the filtrate was neutralized
with aqueous saturated solution of sodium hydrogenocarbonate. The organic
phase was dried over sodium sulfate and concentrated in vacuo. The
residue was purified by column chromatography (ethyl acetate/cyclohexane)
to afford the title product as a brown solid (2.04 g). 1H-NMR
(CDCl3, 400 MHz): 8.40 (s, 1H), 7.60 (s, 1H), 2.30 (s, 3H),

Step B: 5-Bromo-4-methyl-pyridine-2-carbaldehyde

##STR00069##

[0317] In an oven-dried flask the compound obtained in Step A (4.67 g) was
dissolved in tetrahydrofuran (22 ml). The solution was cooled to
-15° C., then isopropyl magnesium bromide (17.2 ml, 15% solution
in THF) was added dropwise at a rate to keep the internal temperature
between -15° C. to -10° C. The reaction was stirred at this
temperature for 1 hour, then anhydrous dimethylformamide (1.8 ml) was
added at a rate to keep the internal temperature below 0° C. The
reaction was stirred at this temperature for 1 hour, then poured into
water and extracted with diethyl ether. The organic layer was dried over
sodium sulfate and concentrated in vacuo. The crude title aldehyde
product (2.4 g, brown solid) was used as such in the next step.

Step C: 5-Bromo-4-methyl-pyridine-2-carbaldehyde oxime

##STR00070##

[0318] To a solution of the compound obtained in Step B (3.1 g) in EtOH
(47.5 ml) and water (23 ml) were added hydroxylamine hydrochloride (1.4
g) and sodium acetate (1.9 g). The reaction was stirred for 15 min at
room temperature. The white solid was filtered off and the solution
concentrated in vacuo to afford the crude title product (2.2 g, white
solid), which was used directly for the next step. LCMS (Method F) 2.09
min, M+H 564/566.

[0321] The reaction was performed under carbon monoxide at 15 bar at room
temperature for 20 min. The reaction mixture was then diluted in toluene
and the suspension was filtered on Celite and washed with toluene. The
solvent was removed under reduced pressure to obtain a red oil. The
residue was purified by column chromatography (ethyl acetate,
cyclohexane) to yield the butyl ester of the title product as a liquid
(3.45 g). 1H-NMR (CDCl3, 400 MHz): 9.03 (s, 1H), 7.90 (s, 1H),
7.50 (s, 2H), 7.40 (s, 1H), 4.35 (t, 2H), 4.25 (d, 1H), 3.90 (d, 1H),
2.55 (s, 3H), 1.80 (q, 2H9, 1.50 (q, 2H), 1.00 (t, 3H). This ester was
dissolved in tetrahydrofuran (8 ml), and sodium hydroxide (0.58 g) in
methanol (8 ml) and water (16 ml) was added dropwise. The reaction
mixture was stirred at room temperature for 3 hours, diluted with ethyl
acetate and acidified with 1N hydrochloric acid. The aqueous layer was
extracted with ethyl acetate and the combined organic layers were dried
over sodium sulfate then concentrated in vacuo. The residue was
triturated in heptane and filtered to obtain the title product as a beige
solid (2 g). LCMS (Method F) 2.22 min, M+H 419/421.

[0322] The title compound was obtained by coupling the carboxylic acid
obtained in Step E (0.15 g) with
(R)-4-Amino-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-3-one (0.10 g,
obtained as described in Example 3 for the preparation of compound B5) as
described in Example 12, Step C. The title product was obtained as a
white solid (48 mg). M.p. 53-55° C. LCMS (Method F) 2.13 min, M+H
583/585.

[0323] The following compound was prepared following a similar method to
that described in Example 17:
6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4-
-methyl-N--[(R)-3-oxo-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-4-yl]-nicotin-
amide (compound C7).

[0324] Similarly, when this reaction was carried out to obtain
2-methyl-N--[(R)-3-oxo-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-4-yl]-4-[5--
(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benz-
amide (compound C8), it was possible to separate the two diastereoisomers
by precipitation after the purification by column chromatography. The
product obtained after column chromatography was thus stirred with
diethyl ether and a solid precipitated out of the solution. The solid
(enriched in one diastereomer) was analysed by chiral HPLC (method K):
8.90 min (91.02%), 11.97 min (08.98%). The filtrate (enriched in the
other diastereomer) was also analysed by chiral HPLC (method K): 8.66 min
(17.50%), 11.02 min (69.38%).

[0325] Similarly, when this reaction was carried out to obtain
4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-
l-3-yl]-2-methyl-N--[(R)-3-oxo-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-4-yl-
]-benzamide (compound C9), it was possible to separate the two
diastereoisomers by precipitation after the purification by column
chromatography. The residue was stirred with diethyl ether and a solid
precipitated out of the solution. The solid (enriched in one
diastereomer) was analysed by chiral HPLC (method K): 8.31 min (87.79%).
The filtrate (enriched in the other diastereomer) was also analysed by
chiral HPLC (method K): 8.28 min (18.15%), 10.75 min (81.85%).

EXAMPLE 18

General Method for Preparing the Compounds of the Invention in Parallel

##STR00074##

[0327] To a solution of a benzoic acid of the formula (IIh) (20 μmol)
in N,N-dimethylacetamide ("DMA") (0.4 ml) was added successively a
solution of an amine of the formula (IIIh) (26 μmol) in
N,N-dimethylacetamide ("DMA") (0.4 ml), diisopropylethylamine (Hunig's
Base) (0.03 ml), and a solution of bis(2-oxo-3-oxazolidinyl)phosphonic
chloride ("BOP-Cl") (10.2 mg) in N,N-dimethylacetamide ("DMA") (0.2 ml).
The reaction mixture was stirred at 90° C. for 16 hours. The
reaction mixture was concentrated and the crude mixture was redissolved
in acetonitrile/N,N-dimethylacetamide (4:1) (0.8 ml) and purified by
HPLC. This method was used to prepare a number of compounds (Compound
Nos. H1 to H26 of Table H) in parallel. The starting carboxylic acids
used for the preparation of compounds of Table H were obtained as
described in Examples 19 to 31.

[0333] The title product was prepared from
5-bromo-quinoline-8-carbaldehyde using the same synthetic route described
in Example 17, Steps C-E.

[0334] 5-Bromo-quinoline-8-carbaldehyde was prepared as follows:

Step A: 5-Bromo-8-methyl-quinoline

##STR00078##

[0335] A solution of 5-Bromo-2-methylaniline (7.44 g), glycerol (7.4 g),
nitrobenzene (4.9 g) in 75% sulfuric acid (20 ml) was heated at
150° C. for 3 hrs. The solution was cooled to 0° C. then
carefully neutralized with aqueous sodium hydroxide. The reaction mixture
became a dark gum and was diluted with water and extracted three times
with ethyl acetate. The combined organic layers were washed with
saturated brine, then dried with sodium sulphate and the solvent removed
in vacuo. The crude product was purified by column chromatography
(dichloromethane) to afford the title compound as a solid (6 g).
1H-NMR (CDCl3, 400 MHz) 8.91 (m, 1H), 8.51 (m, 1H), 7.7 (m,
1H), 7.50 (m, 1H), 7.4 (m, 1H), 2.72 (s, 3H).

Step B: 5-Bromo-8-dibromomethyl-quinoline

##STR00079##

[0336] Radical dibromination was performed using standard method from the
compound obtained in Step A (4.4 g), N-bromo-succinimide (8.9 g) in
tetrachloromethane (200 ml) at reflux for 12 hours in the presence of
dibenzoyl peroxide (245 mg). At the end of the reaction, the succinimide
was filtered off, the solvent was removed in vacuo, and the crude product
used as such for the next step. 1H-NMR (CDCl3, 400 MHz) 8.90
(m, 1H), 8.45 (dd, 1H), 8.15 (d, 1H), 8.10 (s, 1H), 7.80 (d, 1H), 7.45
(m, 1H).

Step C: 5-Bromo-quinoline-8-carbaldehyde

##STR00080##

[0337] Hydrolysis of the dibromo compound obtained using the method
described in Step B (9 g) was carried out in acetone (138 ml) and water
(23 ml) in the presence of silver nitrate (9.7 g) in the dark at room
temperature for 5 hours. The silver salts were filtered off through a pad
of Celite. The filtrate was diluted with ethyl acetate (150 ml),
transferred to a separatory funnel, then washed successively with
saturated aqueous sodium bicarbonate (100 ml), water (3×50 ml), and
brine (50 ml). The organic layer was dried over sodium sulphate filtered,
and evaporated under reduced pressure to afford the title product (4.70
g) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) 11.4 (s, 1H, CHO)
9.05 (m, 1H), 8.61 (dd, 1H), 8.15 (d, 1H), 8.0 (d, 1H), 7.60 (m, 1H)

[0339] This compound was prepared from 5-formyl-pyridine-2-carboxylic acid
methyl ester using the standard synthesis described in WO 2009/080250.
5-Formyl-pyridine-2-carboxylic acid methyl ester was synthesized by
reductive formylation of 5-bromo-pyridine-2-carboxylic acid methyl ester
using the conditions described in Angewandte Chemie, International
Edition (2006), 45(1), 154-158.

[0341] This acid was prepared from the methyl ester of
2-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-benzoic acid (Example 27) as follows:

[0342] A solution of cyclopropyl boronic acid (0.67 g),
2-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-benzoic acid methyl ester (3 g) and
Bis(triphenylphosphine)palladium(II) chloride (210 mg) were sequentially
added to degassed toluene (38 ml). The reaction mixture was stirred for
30 min at room temperature then a degassed aqueous 2N solution of
potassium phosphate (7 ml) was added and the resulting mixture was heated
at 110° C. overnight. The reaction mixture was filtered over Hyflo
and the resulting solution was concentrated in vacuo to give a yellow
oil, which was poured into ethyl acetate. The organic phase was washed
with water, dried over sodium sulfate, and the solvents were evaporated
in vacuo. The product was used as such for the saponification step, as
described in Example 17, Step E to afford the title acid compound (2.5 g)
as a yellow solid. LCMS (Method F) 2.15 min M-H 442/444.

[0344] To a solution of Bis(1,5-cyclooctadiene)dimethoxydiiridium (35 mg)
in hexane (10 ml) under argon was added
4,4'-Di-tert-butyl-2,2'-bipyridine (110 mg). To this dark brown
suspension was added pinacol diborane (2.23 g) and the solution was
stirred at room temperature for 5 min. To this solution was added
2,6-Dichloro-benzonitrile (1 g) and the mixture was heated at 50°
C. for 22 hours. The solution was then filtered on a Celite pad and the
filtrate was concentrated. The residue was then dissolved with ethyl
acetate and extracted with saturated ammonium chloride. The organic layer
was washed with water, dried over sodium sulfate and concentrated. The
residue was used as such in the next reaction.

Step B

[0345] To a solution of crude
2,6-dichloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitril-
e (2.32 g) in a 4:1 mixture THF/H2O (63 ml) was added sodium
periodate (5.01 g). The solution was stirred for 30 min. At room
temperature aqueous hydrochloric acid (1N, 5.5 ml) was added to the
suspension. The solution was further stirred at room temperature for 6
hours then water and diethyl ether were added and the phases were
separated. The organic layer was washed with water, dried over sodium
sulfate and concentrated. The residue was used as such in the next
reaction.

Step C

[0346] To a solution of crude 2,6-dichloro-4-(boronic acid)-benzonitrile
(1.2 g) in a 2:1 mixture THF/H2O (27 ml) was added
2-Bromo-3,3,3-trifluoro-propene (1.2 ml), potassium carbonate (1.54 g),
and then 1,3-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene(1,4-naphthoqui-
none)palladium (438 mg). The reaction mixture was stirred at 60° C.
for 3 hours. The solution was allowed to cool to room temperature and
then filtered on a Celite pad. The filtrate was concentrated undervacuo
and the residue was then dissolved with diethyl ether, extracted with
water, dried over magnesium sulfate and concentrated. The residue was
purified by chromatography on silica gel to give
2,6-Dichloro-4-(1-trifluoromethyl-vinyl)-benzonitrile (1.37 g).
19F-NMR (CDCl3, 75 MHz): -64.65 ppm.

[0349] To a solution of 3-Trifluoromethoxy-benzeneboronic acid (2.5 g) in
a 2:1 mixture THF/H2O (36 ml) was added
2-Bromo-3,3,3-trifluoro-propene (3.1 ml), potassium carbonate (3.35 g),
then Bis(triphenylphosphine)palladium(II) dichloride (169 mg). The
reaction mixture was stirred at 60° C. for 7 hours. The solution
was allowed to cool to room temperature then filtered on a Celite pad.
The filtrate was concentrated in vacuo and the residue was then dissolved
with ethyl acetate, extracted with water, dried over magnesium sulfate
and concentrated. The residue was purified by chromatography on silica
gel to give 1-Trifluoromethoxy-3-(1-trifluoromethyl-vinyl)-benzene (1.23
g). 19F-NMR (CDCl3, 75 MHz): -57.87 ppm and -64.94 ppm.

[0350] To a solution of 4-(hydroxyimino-methyl)-2-methyl-benzoic acid
tert-butyl ester (1.47 g) in N, N-dimethylformamide (13 ml) was added
N-chlorosuccinimide ("NCS") (832 mg). The reaction mixture was stirred at
ambient temperature for 2 hours. More N-chlorosuccinimide ("NCS") (850
mg) was added and the reaction mixture was stirred at ambient temperature
for 1 hour. A solution of
2,6-Dichloro-4-(1-trifluoromethyl-vinyl)-benzonitrile (1.37 g) and
triethylamine (0.72 ml) in N,N-dimethylformamide (13 ml) was added
dropwise to the reaction mixture. The reaction mixture was stirred at
ambient temperature for 17 hours. Water and ethyl acetate were added and
the phases were separated. The organic layer was washed with water, dried
over sodium sulfate and concentrated. The residue was purified by
chromatography on silica gel to give
4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-2-methyl-benzoic acid tert-butyl ester (0.902 g). 19F-NMR
(CDCl3, 75 MHz): -78.93 ppm.

[0371] To a solution of benzoic acid
4-[chloro(hydroxyimino)methyl]-2-(trifluoromethyl) tert-butyl ester
(prepared according to WO 2009/080250) (1.25 g) and
1,3-dichloro-5-[1-(chloro-difluoro-methyl)-vinyl]-benzene (1.19 g)
(prepared according to WO 2005/085216) in dichloromethane (30 ml)
triethylamine (1.9 ml) was added. The reaction mixture was filtered over
a plug of silica and concentrated to give (1.95 g)
4-[5-(Chloro-difluoro-methyl)-5-(3,5-dichloro-phenyl)-4,5-dihydro-isoxazo-
l-3-yl]-2-methyl-benzoic acid tert-butyl ester (1.69 g) which was used in
the following step without any further purification.

[0383] Following the general procedure described in Example 18, several
compounds of formula (Ij) were prepared in parallel (compounds J1-J32 in
Table J). Two diastereoisomers were separated in each case, named A and B
in Table J.

[0393] This Example illustrates the pesticidal/insecticidal properties of
compounds of formula (I). Tests were performed as follows:

Spodoptera littoralis (Egyptian cotton leafworm):

[0394] Cotton leaf discs were placed on agar in a 24-well microtiter plate
and sprayed with test solutions at an application rate of 200 ppm. After
drying, the leaf discs were infested with 5 L1 larvae. The samples were
checked for mortality, feeding behavior, and growth regulation 3 days
after treatment (DAT).

[0395] The following compounds gave at least 80% control of Spodoptera
littoralis:

[0396] Eggs (0-24 h old) were placed in 24-well microtiter plate on
artificial diet and treated with test solutions at an application rate of
200 ppm (concentration in well 18 ppm) by pipetting. After an incubation
period of 4 days, samples were checked for egg mortality, larval
mortality, and growth regulation.

[0397] The following compounds gave at least 80% control of Heliothis
virescens:

[0399] 24-well microtiter plate (MTP) with artificial diet was treated
with test solutions at an application rate of 200 ppm (concentration in
well 18 ppm) by pipetting. After drying, the MTP's were infested with L2
larvae (7-12 per well). After an incubation period of 6 days, samples
were checked for larval mortality and growth regulation.

[0400] The following compounds gave at least 80% control of Plutella
xylostella:

[0402] A 24-well microtiter plate (MTP) with artificial diet was treated
with test solutions at an application rate of 200 ppm (concentration in
well 18 ppm) by pipetting. After drying, the MTP's were infested with L2
larvae (6-10 per well). After an incubation period of 5 days, samples
were checked for larval mortality and growth regulation.

[0403] The following compounds gave at least 80% control of Diabrotica
balteata:

[0405] Sunflower leaf discs were placed on agar in a 24-well microtiter
plate and sprayed with test solutions at an application rate of 200 ppm.
After drying, the leaf discs were infested with an aphid population of
mixed ages. After an incubation period of 7 days, samples were checked
for mortality.

[0406] The following compounds gave at least 80% control of Thrips tabaci:

[0408] Bean leaf discs on agar in 24-well microtiter plates were sprayed
with test solutions at an application rate of 200 ppm. After drying, the
leaf discs are infested with mite populations of mixed ages. 8 days
later, discs are checked for egg mortality, larval mortality, and adult
mortality.

[0409] The following compounds gave at least 80% control of Tetranychus
urticae: